Dose Intensity Research Articles

Safety and efficacy of amrubicin with primary prophylactic pegfilgrastim as second-line chemotherapy in patients with small cell lung cancer.

Amrubicin (AMR) regimens have shown efficacy as second-line treatment in patients with small cell lung cancer (SCLC); however, adverse events such as febrile neutropenia (FN) sometimes preclude their use. Further, the safety and efficacy of AMR with primary prophylactic pegfilgrastim (P-PEG) have not been sufficiently evaluated. In this study, we evaluated the safety and efficacy of AMR with or without P-PEG as second-line chemotherapy for SCLC. We retrospectively reviewed patients with SCLC who received AMR as second-line chemotherapy at Shizuoka Cancer Center, between December 2014 and November 2021. Based on presence/absence of P-PEG in their regimen, patients (n = 60) were divided into P-PEG (n = 21) and non-P-PEG groups, and their clinical outcomes were evaluated. Median of AMR treatment cycles was five (range: 1-39 cycles) in P-PEG group and four (range: 1-15 cycles) in non-P-PEG group. The incidence of FN (4.8% vs. 30.8%; p = 0.02) and AMR dose reduction because of adverse events (4.8% vs. 25.6%; p = 0.08) were lower in the P-PEG group than in the non-P-PEG group. The objective response rates were 52.4% and 30.8%, and median progression-free and overall survival were 4.7 and 3.0 months, and 9.6 and 6.8 months, in the P-PEG and non-P-PEG groups, respectively. AMR with P-PEG as second-line chemotherapy for SCLC reduced the incidence of FN at a maintained AMR dose intensity and was associated with favorable tumor responses and survival outcomes. P-PEG should be considered for patients treated with AMR for SCLC including refractory relapsed SCLC.

Delivered relative dose intensity in adolescent and young adult germ cell tumours in England: Assessment of data quality and consistency from clinical trials compared to national cancer registration data.

Adolescent and young adults (AYA) with germ cell tumours (GCT) have poorer survival rates than children and many older adults with the same cancers. There are several likely contributing factors to this, including the treatment received. The prognostic benefit of intended dose intensity is well documented in GCT from trials comparing regimens. However, evidence specific to AYA is limited by poor recruitment of AYA to trials and dose delivery outside trials not being well examined. We examined the utility of cancer registration data and a clinical trials dataset to investigate the delivery of relative dose intensity (RDI) in routine National Health Service practice in England, compared to within international clinical trials. Linked data from the Cancer Outcomes and Services Dataset (COSD) and the Systemic Anti-Cancer Therapy (SACT) dataset, and data from four international clinical trials were analysed. Survival over time was described using Kaplan-Meier estimation; overall, by age category, International Germ-Cell Cancer Collaborative Group (IGCCCG) classification, stage, tumour subtype, primary site, ethnicity and deprivation. Cox regression models were used to determine the fully adjusted effect of RDI on mortality risk. The quality of both datasets was critically evaluated and clinically enhanced. RDI was found to be well maintained in all datasets with higher RDIs associated with improved survival outcomes. Real-world data demonstrated several strengths, including population coverage and inclusion of sociodemographic variables and comorbidity. It is limited in GCT however, by the poor completion of data items enabling risk classification of patients and a higher proportion of missing data.

Beam Effects on Atomic Dynamics in Metallic Glasses Studied With Electron Correlation Microscopy.

Electron correlation microscopy (ECM) is used to investigate atomic dynamics in metallic glasses (MG) close to metastable equilibrium. It temporally correlates diffracted intensities of a time series of dark-field images to deduce a metric for structural decays. The measurement parameters, such as time and temperature, must be chosen according to the material of interest. In this work, ECM was extended to measurements at room temperature. To ensure, or select, a time window with quasi-thermodynamic equilibrium/steady-state measurement conditions, two-time correlation functions of diffracted intensities were calculated. The dynamics at room temperature are partly driven by the electron beam, thus affecting the material and the results. A systematic analysis of the influence of the electron beam is presented, revealing an inverse relation between electron dose rate and intensity correlation decay times at 300 kV acceleration voltage. However, the underlying dynamical mechanisms, described by a stretching exponent, are found to be independent of the applied electron dose rate for a Pd40Ni40P20 MG. An extrapolation of the results to infinite long measurement times and zero dose rate agrees with X-ray photon correlation spectroscopy data and justifies the application of beam-driven ECM at room temperature to study the dynamics of disordered systems.

Geriatric Nutritional Risk Index Predicts Tolerability of S-1 as Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma.

Surgery plus adjuvant chemotherapy (AC) for resectable pancreatic ductal adenocarcinoma (PDAC) has been shown to prolong survival compared with surgery alone. Thus, it is of clinical importance that these patients receive a continuous dose of S-1. The aim of this study was to examine whether the geriatric nutritional risk index (GNRI) is a predictor for the completion of S-1 as AC for PDAC. Seventy-seven patients who were administered S-1 as AC after pancreatectomy for PDAC between January 2010 and October 2021 were retrospectively enrolled. Predictive markers were statistically analyzed for S-1 completion, which was defined as continued oral administration with relative dose intensity of >80%. Patients were divided into the S-1 complete group (n = 55; 71.4%) and S-1 incomplete group (n = 22; 28.6%). There was a significant association of higher GNRI (P = 0.013) at the onset of AC with the completion of S-1. Receiver operating characteristic curve analysis revealed 94.4 as the optimal cutoff value of GNRI for predicting the completion of S-1. Univariate and multivariate analyses confirmed that GNRI >94.4 was independently associated with the completion of S-1 (P = 0.007). High GNRI value is a predictive marker for the completion of S-1 as AC for PDAC.

Real-Time TDM-Based Expert Clinical Pharmacological Advice Program for Attaining Aggressive Pharmacokinetic/Pharmacodynamic Target of Continuous Infusion Meropenem in the Treatment of Critically Ill Patients with Documented Gram-Negative Infections Undergoing Continuous Veno-Venous Hemodiafiltration.

(1) Objectives: to describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of continuous infusion (CI) meropenem in critical patients with documented Gram-negative infections undergoing continuous veno-venous hemodiafiltration (CVVHDF) and to assess the relationship with microbiological outcome. (2) Methods: Data were retrospectively retrieved for patients admitted to the general and the post-transplant intensive care units in the period October 2022-May 2023 who underwent CVVHDF during treatment with CI meropenem optimized by means of a real-time therapeutic drug monitoring (TDM)-based expert clinical pharmacological advice (ECPA) program for documented Gram-negative infections. Steady-state meropenem plasma concentrations were measured, and the free fractions (fCss) were calculated. Meropenem total clearance (CLtot) was calculated at each TDM assessment, and the impact of CVVHDF dose intensity and of residual diuresis on CLtot was investigated by means of linear regression. Optimal meropenem PK/PD target attainment was defined as an fCss/MIC ratio > 4. The relationship between meropenem PK/PD target attainment and microbiological outcome was assessed. (3) Results: A total of 24 critical patients (median age 68 years; male 62.5%) with documented Gram-negative infections were included. Median (IQR) meropenem fCss was 19.9 mg/L (17.4-28.0 mg/L). Median (IQR) CLtot was 3.89 L/h (3.28-5.29 L/h), and median (IQR) CVVHDF dose intensity was 37.4 mL/kg/h (33.8-44.6 mL/kg/h). Meropenem dosing adjustments were provided in 20 out of 24 first TDM assessments (83.3%, all decreases) and overall in 26 out of the 51 total ECPA cases (51.0%). Meropenem PK/PD target attainment was always optimal, and microbiological eradication was achieved in 90.5% of assessable cases. (4) Conclusion: the real-time TDM-guided ECPA program was useful in attaining aggressive PK/PD targeting with CI meropenem in critically ill patients undergoing high-intensity CVVHDF and allowed microbiological eradication in most cases with dosing regimens ranging between 125 and 500 mg q6h over 6 h.

Association of NUDT15 gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis.

6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosupression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3,374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (odds ratio [OR] =9.00, 95% confidence interval [CI]: 3.73-21.74) and 2.5-fold higher risk of 6-MP-induced neutropenia (OR=2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild-type patients (CC) (mean differences: 19.43%, 95% CI: -25.36 to -13.51). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild-type patients, respectively. The NUDT15 c.415C>T variant group (CT+TT) had seven times (OR=6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP-induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild-type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP.

An observational, prospective, open label, multicenter study to evaluate the safety and effectiveness of pegfilgrastim as secondary prophylaxis to decrease the incidence of febrile neutropenia in Korean female patients with breast cancer

PurposePegfilgrastim is a widely used long-acting granulocyte colony-stimulating factor (G-CSF) that prevents febrile neutropenia (FN) in patients with breast cancer receiving chemotherapy. This study aimed to evaluate the incidence of chemotherapy-related FN events and other adverse events (AEs) during chemotherapy in Korean patients with breast cancer treated with pegfilgrastim as secondary prophylactic support. Materials and methodsThis was a multicenter, open-label, prospective, observational study. A total of 1255 patients were enrolled from 43 institutions. The incidence of FN was evaluated as the primary endpoint. The secondary endpoints included (1) incidence of bone pain, (2) proportion of patients with a relative dose intensity (RDI) of ≥85%, and (3) proportion of patients with AE. ResultsPegfilgrastim administration reduced FN by 11.8–1.6%. The highest incidence of bone pain was observed at the time point of the 1st day after the administration and mild bone pain was the most common of all bone pain severity. The mean RDI was 98.5 ± 7.3%, and the proportion of the patients with and RDI≥85% was 96.9% (1169/1233). AEs were reported in 52.6% of the patients, and serious drug reactions occurred in only 0.7%. ConclusionThe use of pegfilgrastim as secondary prophylaxis was effective and safe for preventing FN in patients with breast cancer who were treated with chemotherapy.

A Prospective Phase II Dose Escalation Study Using IMRT for High Risk N0M0 Prostate Cancer.

Published data supports the use of very high dose intensity modulated radiotherapy (IMRT) in achieving high efficacy and low toxicity for high-risk prostate cancer (HRPCa). This phase II multi-institutional non-randomized prospective dose escalation study using intensity modulated radiotherapy (IMRT) for high risk N0M0 prostate cancer was designed to investigate dose escalation using 1.8 Gy increments from baseline 75.6 Gy up to maximum 81 Gy, once dose volume constraints were adhered to. Inclusion criteria were patients undergoing a radical course of RT for high and very high-risk disease, defined as one or more of the criteria ≥ T3*, ≥ Gleason 8, Prostate specific antigen (PSA) > 20ng/ml. All patients received Androgen Deprivation Therapy (ADT) and none had radiological evidence of distant metastatic disease. The primary objective was to determine if dose escalated IMRT for high risk localized prostate cancer could provide freedom from biochemical relapse (BR; PSA rising > nadir +2ng/mL or initiation of salvage hormone therapy) similar to that reported in the literature. The Kaplan-Meier method was used to estimate survival times. Secondary objectives included OS, Disease Free Survival (DFS), and the incidence and severity of Genito-urinary (GU), Gastro-intestinal (GI) and erectile dysfunction (ED) toxicities (CTCAE v.3). Toxicities and performance status were collected and graded weekly during RT, 2 months after completing RT, 8 months' post RT, and 6 monthly thereafter to year five and annually thereafter to year nine. A total of 230 evaluable patients were enrolled between April 2009 and June 2016. The median follow-up was 7.3 years. The cumulative proportion of patients surviving without BR at 5 years was 91% (95% Confidence Interval (CI): 86% to 94%). Overall survival at 5 and 7 years was 92% (88% to 95%) and 89% (83% to 92%) respectively, while the cumulative proportion of patients free from disease was 89% (84% to 93%) at 5 years and 81% (75% to 86%) at 7 years. The incidence of acute G2 and G3 toxicities were; GU; 57.8% G2, 12.6% G3, GI; 15.2% G2, 0.4% G3, ED; 30.0% G2 and 61.7% G3. The incidence of late G2, G3 and G4 toxicities were; GU; 40.9% G2, 8.7% G3, GI; 36.5% G2, 2.2% G3, 0.4% G4, ED; 11.7% G2 and 86.1% G3. The percentage of patients receiving each dose level was; 3.5% received 75.6Gy in 42 fractions, 2.2% received 77.4Gy in 43 fractions, 93% received 81Gy in 45 fractions. The findings indicate that high-dose IMRT is well tolerated and is associated with excellent long-term tumor-control outcomes in patients with localized high and very high-risk prostate cancer, with 91% of patients surviving at 5 years without biochemical relapse. The rates of long term G3 GU and GI toxicity were low at 8.7% and 0.4% respectively.

Vers une dé-escalade des traitements par immunothérapie des CBNPC avancés : pourquoi, comment ?: De-escalation strategy with immune check-point blockers in advanced non-small cell lung cancer

Since the advent of immune checkpoint inhibitors (ICIs), the prognosis of non-small cell lung cancer (NSCLC) has undergone a profound transformation. Nonetheless, the use of these agents in terms of dosing, treatment duration, and dosing frequency remains suboptimal. Indeed, a body of evidence suggests that we could potentially use regimens with a lower dose intensity compared to the approved doses. This bears significant implications in terms of cost, and maybe quality of life, and toxicities. The pursuit of optimal immunotherapeutic regimens presents a considerable challenge. This manuscript attempts to synthesize the rationale and modality of optimizing ICI-based treatment and the ongoing trials testing this hypothesis.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Comprehensive Beam Modeling, Secondary Dose Computations and Treatment Planning for a 1.5 T MRgRT System

Magnetic resonance imaging guided radiotherapy (MRgRT) combines soft tissue visualization with online adaptive radiotherapy. The MRgRT workflow is characterized by many steps which needs to be performed swiftly and therefore greatly benefits from automation. The purpose of this study was to model a MRgRT system for dose computation and intensity modulated radiotherapy (IMRT) planning within a 1.5 T magnetic field in an independent treatment planning system (iTPS) with automation functionalities. A beam model for a 1.5 T MRgRT system was commissioned in an iTPS using beam profiles and output factor measurements. The cryostat of the MRgRT system was modeled using a cylindrical multi-layer combination of epoxy and aluminum and matched to source-to-surface dependent cryostat scatter measurement in air, and corrected for angular dependent cryostat transmission readings. The beam model was used with a fast Monte Carlo dose engine to account for the electron return and electron streaming effects within an external magnetic field. The multi-leaf collimator (MLC) was characterized with a novel synchronous and asynchronous sweeping gap (aSG) test. The aSGs have a shift (between 0 - 40 mm) between adjacent leaves which remains constant over the sweep. Measured doses map the shadowing due to the tongue-and-groove (TG) exposure and TG and leaf tip (LT) parameters are derived to match this within the iTPS. Clinical IMRT plans of 10 prostate, 5 lymph node and 5 rectal plans created in the default clinical TPS were recomputed in the iTPS and evaluated with the corresponding plan-specific quality assurance measurements. In addition, three IMRT plans were optimized within the iTPS, delivered with the MRgRT system and evaluated using PSQA using a 3%/3mm gamma criterium with a 10% threshold. Monte Carlo dose computation in the iTPS closely resembled the measured profiles in the presence of the 1.5 T magnetic field. The cryostat scatter simulations were <0.7% compared to the measurements and literature. The aSG/SGs test demonstrated that the TG width gradually increased up to 1 mm for a distance of 15 mm away from the leaf tip end. These effects were closely replicated in the iTPS with a difference of <1.5% for 95% of the aSGs. The difference between the clinical dose and the dose calculation in the iTPS was, on average, <0.5% within the volume receiving 50% of the maximum dose. The gamma pass rate was 100% for 98% of the PSQA results. The plans optimized within the iTPS were successfully delivered at the MRgRT system. We successfully modeled and commissioned a 1.5 T MRgRT system in an independent TPS. The beam model can be used for a second opinion dose computation in a magnetic field and for direct treatment planning. Next, the beam model will be incorporated in a semi-automated and adaptive workflow using the iTPS.

The Efficacy and Safety of a Low Relative Dose Intensity of Cabazitaxel in Patients With Metastatic Castration-resistant Prostate Cancer.

Clinical trials have shown that the efficacy of a reduced dose of cabazitaxel (20 mg/m2 every 3 weeks) was not inferior to that of the standard dose (25 mg/m2 every 3 weeks). However, the efficacy of even lower relative dose intensities, such as 20 mg/m2 every 4 weeks, have not been evaluated conclusively. The aim of this study was to investigate the efficacy and safety of a low relative dose intensity of cabazitaxel in patients with metastatic castration-resistant prostate cancer in the real world. We retrospectively analyzed 101 consecutive patients treated with cabazitaxel for docetaxel-refractory metastatic castration-resistant prostate cancer. The progression-free and overall survival after introduction of cabazitaxel and prostate-specific antigen response rate were assessed as oncological outcome measures. The patients were divided into two groups (relative dose intensity >60%, n=74 and ≤60%, n=27). Both progression-free and overall survivals were significantly better in the >60% group than in the ≤60% group (median 5 and 2 months, p<0.01, and 15 and 6 months, p<0.01, respectively). In multivariate analyses, visceral metastasis and relative dose intensity ≤60% were prognostic factors for shorter progression-free and overall survivals (p=0.04, p<0.01, respectively). The incidence of adverse events was not significantly different between groups. The cabazitaxel relative dose intensity ≤60% group had significantly shorter progression-free and overall survivals than the >60% group, whereas the incidence of adverse events was not significantly different. The results suggested that reducing the relative dose intensity of cabazitaxel to ≤60% may not be recommended.

How do we define high and low dose intensity of heart failure medications: a scoping review

BackgroundOlder adults with heart failure often experience adverse drug events with high doses of heart failure medications. Recognizing whether a patient is on a high or low dose intensity heart failure medication can be helpful for daily practice, since it could potentially guide the physician on which symptoms to look for, whether from overdosing or underdosing. However, the current guideline does not provide sufficient information about the dose intensity below the target dose. Furthermore, the definition of high or low-intensity heart failure medication is unclear, and there is no consensus.MethodsTo close the knowledge gap, we conducted a scoping review of the current literature to identify the most frequently used definition of high versus low doses of heart failure medications. We searched Pubmed, Embase, CINAHL, and Cochrane Library using comprehensive search terms that can capture the intensity of heart failure medications.ResultsWe reviewed 464 articles, including 144 articles that had information about beta-blockers (BB), 179 articles about angiotensin-converting enzyme inhibitors (ACEi), 75 articles about angiotensin receptor blockers (ARB), 80 articles about diuretics, 37 articles about mineralocorticoid receptor antagonists (MRA), and 33 articles about angiotensin receptor-neprilysin inhibitor (ARNI). For hydralazine with isosorbide dinitrate or ivabradine, we could not identify any eligible articles. We identified 40 medications with most frequently used definitions of dose intensity. Four medications (nadolol, pindolol, cilazapril, and torsemide) did not reach consensus in definitions. Most of the BBs, ACEis, or ARBs used the definition of low being < 50% of the target dose and high being ≥ 50% of the target dose from the guideline. However, for lisinopril and losartan, the most commonly used definitions of high or low were from pivotal clinical trials with a pre-defined definition of high or low.ConclusionOur comprehensive scoping review studies identified the most frequently used definition of dose intensity for 40 medications but could not identify the definitions for 4 medications. The results of the current scoping review will be helpful for clinicians to have awareness whether the currently prescribed dose is considered high - requiring close monitoring of side effects, or low - requiring more aggressive up-titration.

Reducing chemotherapy dose intensity by 25% and adding rituximab improves survival in pediatric mature B-cell non-Hodgkin lymphoma in LMIC setting.

Pediatric B-cell non-Hodgkin lymphomas (NHL) in low- and middle-income countries (LMICs) have historically had inferior outcomes due to higher treatment-related mortality (TRM) and relapses. To address this issue, we evaluated the impact of reducing chemotherapy dose intensity by 25% and adding rituximab on outcomes in pediatric B-NHL. Patients, less than 18years of age with group B and C disease as per the Lymphome Malin de Burkitt (LMB) risk stratification were enrolled between September 2017 and October 2022. The LMB-89 protocol, with a 25% reduction in all chemotherapy doses and the addition of rituximab, was administered. The response was assessed using positron emission tomography with computed tomography (PET/CT) after four cycles of chemotherapy (interim) and at the end of treatment. The study included 25 patients with a median age of 6.9years, among whom 20 (80%) were males. Twenty patients had group B and five had group C disease. Complete metabolic response (CMR) was achieved by 22/25 (88%) patients, and three (12%) achieved partial metabolic response (PMR) in the interim PET/CT. At the end of treatment, 22/24 (92%) patients achieved CMR, one had PMR, and one had progressive disease. The median follow-up was 45months (range: 3-71months). The 4-year event-free survival and overall survival were 88% and 92%, respectively. There were two deaths, one due to disease progression and the other due to sepsis. Our study demonstrates a significant improvement in outcomes in pediatric B-NHL compared to previous reports from LMICs, achieved through a 25% reduction in chemotherapy dose intensity and the addition of rituximab.

Comparison of the outcomes of patients with primary central nervous system lymphoma between the neurosurgery and hematology/oncology departments based on the relative dose intensity of methotrexate.

Primary central nervous system lymphoma (PCNSL) is an extranodal type of lymphoma, which is treated with methotrexate (MTX)-based induction therapy. Although PCNSL is a hematological malignancy, patients with PCNSL may be treated at neurosurgery or hematology/oncology departments; however, the outcomes of PCNSL treatment have not been compared between these two departments. The present study compared the outcomes of 26 patients with newly diagnosed PCNSL that were treated at the Department of Neurological Surgery or Department of Hematology/Oncology (Wakayama Medical University Hospital, Wakayama, Japan) between January 2011 and December 2021. The relative dose intensity (RDI) and relative treatment intensity of MTX were assessed as indicators of the intensity of chemotherapy. The median RDI of MTX was 67 and 93% in the neurosurgery and hematology/oncology groups, respectively (P<0.001). The proportion of patients that achieved a complete response after high-dose MTX-based therapy was significantly higher in the hematology/oncology group than in the neurosurgery group (P=0.038). The estimated 2-year overall survival was 72 and 100% in the neurosurgery and hematology/oncology groups, respectively (P=0.046). As with the difference in the outcomes observed between pediatrics and hematology departments for adolescents with acute lymphoblastic leukemia, the outcomes of patients with PCNSL may differ between neurosurgery and hematology/oncology departments.

Implementing pharmacogenetic testing in fluoropyrimidine-treated cancer patients: DPYD genotyping to guide chemotherapy dosing in Greece.

Introduction: Dihydropyrimidine dehydrogenase (DPD), encoded by DPYD gene, is the rate-limiting enzyme responsible for fluoropyrimidine (FP) catabolism. DPYD gene variants seriously affect DPD activity and are well validated predictors of FP-associated toxicity. DPYD variants rs3918290, rs55886062, rs67376798, and rs75017182 are currently included in FP genetic-based dosing guidelines and are recommended for genotyping by the European Medicines Agency (EMA) before treatment initiation. In Greece, however, no data exist on DPYD genotyping. The aim of the present study was to analyze prevalence of DPYD rs3918290, rs55886062, rs67376798, rs75017182, and, additionally, rs1801160 variants, and assess their association with FP-induced toxicity in Greek cancer patients. Methods: Study group consisted of 313 FP-treated cancer patients. DPYD genotyping was conducted on QuantStudio ™ 12K Flex Real-Time PCR System (ThermoFisher Scientific) using the TaqMan® assays C__30633851_20 (rs3918290), C__11985548_10 (rs55886062), C__27530948_10 (rs67376798), C_104846637_10 (rs75017182) and C__11372171_10 (rs1801160). Results: Any grade toxicity (1-4) was recorded in 208 patients (66.5%). Out of them, 25 patients (12%) experienced grade 3-4 toxicity. DPYD EMA recommended variants were detected in 9 patients (2.9%), all experiencing toxicity (p = 0.031, 100% specificity). This frequency was found increased in grade 3-4 toxicity cases (12%, p = 0.004, 97.9% specificity). DPYD deficiency increased the odds of grade 3-4 toxicity (OR: 6.493, p = 0.014) and of grade 1-4 gastrointestinal (OR: 13.990, p = 0.014), neurological (OR: 4.134, p = 0.040) and nutrition/metabolism (OR: 4.821, p = 0.035) toxicities. FP dose intensity was significantly reduced in DPYD deficient patients (β = -0.060, p <0.001). DPYD rs1801160 variant was not associated with FP-induced toxicity or dose intensity. Triple interaction of DPYD*TYMS*MTHFR was associated with grade 3-4 toxicity (OR: 3.725, p = 0.007). Conclusion: Our findings confirm the clinical validity of DPYD reduced function alleles as risk factors for development of FP-associated toxicity in the Greek population. Pre-treatment DPYD genotyping should be implemented in clinical practice and guide FP dosing. DPYD*gene interactions merit further investigation as to their potential to increase the prognostic value of DPYD genotyping and improve safety of FP-based chemotherapy.

Retrospective analysis of the impact of dose delay and reduction on outcomes of colorectal cancer patients treated with FOLFIRI‑based treatment.

To determine the relationship between chemotherapy dose delay/reduction with progression-free survival (PFS) and overall survival (OS) in colorectal cancer patients treated with FOLFIRI based first-line chemotherapy in real-world retrospectively study. We identified 144 eligible patients with advanced CRC who received FOLFIRI as first-line based treatment. The study protocol was submitted to the institutional review board and was exempted. Dose delay was defined as an average delay of more than 3 days (>3 days vs. ≤3 days) from the intended date. Dose reduction (actual dose/standard dose * 100%) ≤85% was considered as chemotherapy reduction in the chemotherapy dose relative to the standard (mg/m2) regimen for all cycles. Relative dose intensity (RDI) ≤80% was described as chemotherapy reduction. OS and PFS were measured using Kaplan-Meier and Cox proportional hazard models. There were 114 patients with chemotherapy dose delay (dose delay >3 days). PFS of patients without dose delay had better survival than patients with dose delay (p = 0.002). There were 28.47% patients treated with dose reduction of 5-Fu. PFS and OS were better in patients without 5-Fu dose reduction than in patients with 5-Fu dose reduction with p values of 0.024 and <0.001, respectively. Patients with high 5-FU RDI had better PFS than patients with low 5-FU RDI (p < 0.001). While, there was no statistical difference in OS between the two groups. Then we stratified the analysis by age. In <65 years cohort, both PFS and OS were better in patients with high 5-Fu RDI than in those with low 5-Fu RDI (p < 0.001, p = 0.005, respectively). But, in ≥65 years cohort, OS were better in patients with low 5-Fu RDI than in those with high 5-Fu RDI (p = 0.025). Moreover, both dose reduction and RDI of irinotecan had no statistically significant difference in both PFS and OS. In the advanced colorectal cancer patients who received FOLFIRI based treatment as first-line regimen, chemotherapy dose delay and reduction dose of 5-Fu were associated with worse survival, especially among patients younger than 65 years.

P21.06.A TIME IN ONCOLOGY. GLIOBLASTOMA REAL-WORLD DATA

Abstract BACKGROUND Time is a crucial component in all diagnostic and therapeutic processes of cancer. Retard in the treatment can have adverse consequences on outcomes. Total treatment delays could be due to patient interval (from the first perceived symptom to the first medical consultation) and system interval (from the first medical consultation to end of treatment). To minimize delays, it is essential to know the time intervals elapsed between each of the steps in the diagnostic and the treatment phase.The purpose of this pilot study is to holistically analyze the total treatment interval of cancer patients as a part of process-oriented total quality management with the ultimate intention of having more useful information for benchmarking and making decisions to improve time in oncology. MATERIAL AND METHODS During 2019 in a context of public health-care system all relevant clinical pathway time data from the patient’s perceived first symptom until the end of oncological treatment were collected in a prospective cohort of newly diagnosed glioblastoma patients. Clinical pathway is defined as a description of the current practice in an homogeneous patient group treated by a multidisciplinary team and an inventory of actions defining a diagnostic and therapeutic sequence. This cohort was compared with a serie of glioblastoma patients treated in 2020 (COVID-19-year). We analyzed the mean, median and quartile data of 16-time intervals represented on a time scale RESULTS From January 1 to December 31, 2019, we collected data from 59 patients diagnosed and treated for a glioblastoma. There were 24 women and 35 men with a mean age of 60,9 years. We collected 1062 time-points. This group was compared with a COVID-19-year cohort of 49 patients (14 women and 35 men with a mean age of 61,7 years and 630 time-points). The median patient interval time and the system interval time were 6 days (0-210) vs 5 (0-150) and 240 days (81-363) vs 255 (120-482) respectively. Median time from surgery to the start of adjuvancy was 34 days (19-56) vs 34 (17-108). No differences were found in any of the intervals analyzed, in the overall treatment time of radiotherapy or in the dose intensity of chemotherapy. CONCLUSION The routine measurement of the intervals between the different diagnostic and therapeutic actions is essential to monitor the time of clinical processes in terms of quality and benchmarking. It is also essential to standardize in a holistic way the distressing temporality in oncology.

The Relative Dose Intensity Changes during Cycles of Standard Regimens in Patients with Diffuse Large B-Cell Lymphoma.

No studies have focused on the trajectory of the average relative dose intensity (ARDI) during cycles of first-line chemotherapy for patients with diffuse large B-cell lymphoma. To evaluate the impact of attenuating ARDI during cycles on overall survival, we conducted a multi-centre, longitudinal, observational retrospective study. A total of 307 analysable patients were enrolled. Multivariate Cox hazards modelling with restricted cubic spline models revealed prognostic benefits of higher ARDI up to, but not after, cycle 6. According to group-based trajectory modelling, patients were classified into five groups depending on the pattern of ARDI changes. Among these, two groups in which ARDI had fallen significantly to less than 50% by cycles 4-6 displayed significantly poorer prognosis, despite increased ARDI in the second half of the treatment period (log-rank p = 0.02). The Geriatric Nutritional Risk Index offered significant prediction of unfavourable ARDI changes (odds ratio 2.540, 95% confidence interval 1.020-6.310; p = 0.044). Up to cycle 6, maintenance of ARDI in all cycles (but particularly in the early cycles) is important for prognosis. Malnutrition is a significant factor that lets patients trace patterns of ARDI changes during cycles of chemotherapy associated with untoward prognosis.

Primary Prevention of Neutropenia by Empegfilgrastim in Patients with Advanced Stages of Classical Hodgkin Lymphoma Treated with Intensive First-Line Chemotherapy with a Modified 6-Cycle Program EACODD-14 Under the Protocol “LKh-Rossiya-1”

Aim. To assess the efficacy of a long-acting form of the granulocyte colony-stimulating factor (G-CSF) empegfilgrastim in primary prevention of neutropenia in patients with advanced stages of classical Hodgkin lymphoma (cHL) who received intensive chemotherapy with reduced inter-cycle interval under the protocol “LKh-Rossiya-1”.&#x0D; Materials &amp; Methods. The study enrolled 35 patients with newly diagnosed cHL. All patients had advanced stages (IIB X/Е and III/IV) of the disease. They were treated at the NI Pirogov National Medical and Surgical Center from March 2013 to August 2022. The primary prevention of neutropenia by long-acting G-CSF (empegfilgrastim) was administered to 21 patients under the protocol “LKh-Rossiya-1”. They received 6 chemotherapy cycles of modified EACODD-14, in total 126 cycles. The control group consisted of 14 patients who received 6 ЕАСОРР-14 chemotherapy cycles (in total 84 cycles) with dacarbazine as substitution for procarbazine. In the control group, the primary prevention of neutropenia was carried out using discrete G-CSF (filgrastim). The median (range) follow-up in the main (n = 21) and control (n = 14) groups was 18 (5–36) and 39 (29–116) months, respectively. The treatment efficacy was assessed based on PET-CT in 31 patients and on CT in 4 patients.&#x0D; Results. By the end of chemotherapy, complete metabolic response was achieved in 28 (80 %) out of 35 patients (95 % in the EACODD-14 and 73 % in ЕАСОРР-14 groups). In 6 (17 %) patients, partial remission was confirmed only by CT scan, and in 1 (3 %) patient, PET/CT showed stabilization. After consolidation radiotherapy, complete remission was reported in all 35 patients. Both groups received the full chemotherapy program per protocol. Without a violation of G-CSF regimen, the EACODD-14 group received 121 (96 %) cycles out of those 126 planned, whereas the ЕАСОРР-14 group received all 84 cycles per protocol. Full implementation of 107 (88.4 %) cycles in the first group and 24 (29 %) cycles in the second group was achieved in 12 (57 %) and 5 (36 %) patients, respectively (p &lt; 0.001). Neutropenia grade 4 was more often identified in filgrastim than in empegfilgrastim recipients (57 % vs. 19 %; p &lt; 0.05) and in a larger number of cycles (15 % vs. 3 %; p &lt; 0.01). The rate of infection episodes in the ЕАСОРР-14 group was higher (50 % vs. 28 %) and in more cycles (15 % vs. 5 %; p &lt; 0.05). Due to the use of long-acting G-CSF (empegfilgrastim) the number of inpatient days could be reduced from 9 to 5.&#x0D; Conclusion. The results of this study demonstrate the advantage of long-acting G-CSF (empegfilgrastim) as compared with its discrete form (filgrastim) in intensified programs with a reduced inter-cycle interval and high risk of febrile neutropenia (EACODD-14 and EACOРР-14). The use of empegfilgrastim allowed to administer three times as many chemotherapy cycles adhering to the principle of dose intensity in a larger number of patients with advanced cHL stages.

Clinical impact of relative dose intensity of cabozantinib during the first 8 weeks and of subsequent dose reductions in patients with unresectable hepatocellular carcinoma

Clinical impact of relative dose intensity of cabozantinib during the first 8 weeks and of subsequent dose reductions in patients with unresectable hepatocellular carcinoma