Mainly severe (CTCAE grade 3-4) haematotoxicity during peptide receptor radionuclide therapy (PRRT) is reported in literature due to major clinical impact, however moderate (CTCAE grade 2) ...haematotoxicity is common and could affect therapy management. The aim of this study was to evaluate the haematotoxicity course during PRRT and to compare baseline parameters between haematotoxicity grades.
In this retrospective study, 100 patients with a neuroendocrine tumour treated with PRRT were included. Patients were treated with an aimed number of four cycles with 7.4 GBq 177LuLu-DOTA-TATE administered every 10 weeks. Haematological assessment was performed at baseline and frequently up to 10 weeks after the fourth cycle. The lowest haematological value was graded according to CTCAE v5.0, and patients were classified using the highest observed grade. Differences in baseline parameters, including 68GaGa-DOTA-TATE positive tumour volume, were evaluated between CTCAE grades.
Four cycles were completed by 86/100 of patients, 4/100 patients discontinued due to haematotoxicity, and 10/100 patients due to progressive disease. The treatment course was adjusted due to haematotoxicity in 24/100 patients, including postponed next cycle (n = 17), reduced administered activity (n = 13), and both adjustments (n = 10). The most observed haematotoxicity grade was grade 0-1 in 54/100 patients, grade 2 in 38/100 and grade 3-4 in 8/100. Significant differences in baseline leucocyte, neutrophil and platelet counts were observed between grade 0-1 and grade 2. However, the correlation between baseline and lowest observed values was poor to moderate. No differences between haematotoxicity grades and baseline parameters or somatostatin receptor positive tumour volume was observed.
The incidence of severe haematotoxicity was low with extensive screening and monitoring. The vast majority of patients (96/100) was not restricted in treatment continuation by haematotoxicity; therefore, our selection criteria appeared appropriate for safe PRRT treatment. Baseline parameters showed limited correlation with the degree of decline in haematological values.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Paclitaxel is avidly transported by P‐glycoprotein (P‐gp/MDR1/ABCB1). This results in low oral bioavailability, which can be boosted by coadministration of P‐gp inhibitors. Unlike paclitaxel, ...docetaxel is extensively metabolized by CYP3A4 and its oral bioavailability can be enhanced in mice and humans by coadministration of the potent CYP3A inhibitor ritonavir. Unexpectedly, ritonavir also enhances the oral bioavailability of paclitaxel in humans. We aimed to resolve the mechanism underlying this enhancement. Using mice lacking Cyp3a and/or P‐gp, we investigated the combined and separate restricting roles of Cyp3a and P‐gp in the oral bioavailability of paclitaxel, and the boosting effect of ritonavir. CYP3A4‐humanized mice were used for translation to the human situation. P‐gp had a dominant effect (11.6‐fold, p < 0.001) over Cyp3a (<1.5‐fold, n.s.) in limiting plasma concentrations of oral paclitaxel. However, in the absence of P‐gp, Cyp3a decreased paclitaxel plasma concentrations twofold (p < 0.001). Coadministered ritonavir inhibited Cyp3a‐mediated metabolism, but not P‐gp‐mediated transport of paclitaxel. Owing to the dominant effect of P‐gp, ritonavir enhanced only paclitaxel plasma concentrations in P‐gp‐deficient mice. Mouse liver microsomes metabolized paclitaxel far less efficiently than human or CYP3A4‐transgenic liver microsomes, revealing much lower efficiency of paclitaxel metabolism by mouse than by human CYP3As. Accordingly, ritonavir could enhance the oral bioavailability of paclitaxel in CYP3A4‐humanized mice, despite the fact that these mice are P‐gp‐proficient. Our results show that CYP3A4 inhibition most likely underlies the boosting effect of ritonavir on oral paclitaxel bioavailability in humans. Furthermore, CYP3A4‐humanized mice allow improved understanding of CYP3A4‐mediated paclitaxel metabolism in humans.
What's new?
Paclitaxel is used for various malignancies but must be administered intravenously because of poor bioavailability following oral administration. The ATP‐binding cassette (ABC) drug efflux transporter P‐glycoprotein is a well‐known limiting factor in the drug's intestinal uptake, an effect reported here to also be mediated by the enzyme cytochrome P450 3A (CYP3A). The findings suggest that CYP3A inhibition may augment the effects of ritonavir, which enhances paclitaxel bioavailability, and indicate that further study of the drug in mice could lead to new insight into CYP3A4‐mediated paclitaxel metabolism.
Immune checkpoint inhibitors have revolutionised cancer treatment by offering durable responses to many patients with solid and haematological cancers. The high prices and increasing use of immune ...checkpoint inhibitors put considerable strain on health-care budgets globally. This financial strain could jeopardise patients’ access to these anti-cancer therapies. However, substantial evidence suggests that immune checkpoint inhibitors are being administered at doses that exceed the minimum dose required for maximum anti-tumour efficacy. Therefore, investigating and implementing the most cost-effective dosing strategies for immune checkpoint inhibitors are urgently necessary. This Personal View provides an overview of existing data on immune checkpoint inhibitor pharmacology and (novel) dosing strategies for anti-PD-1 therapy with nivolumab and pembrolizumab, with a special focus on cost-effectiveness and saving potential. Furthermore, specific recommendations to guide health-care professionals are provided, through the process of prescribing, rounding, preparing, and administering nivolumab and pembrolizumab in the most practical and cost-effective way possible.
Fixed Dosing of Monoclonal Antibodies in Oncology Hendrikx, Jeroen J.M.A.; Haanen, John B.A.G.; Voest, Emile E. ...
The oncologist (Dayton, Ohio),
October 2017, Letnik:
22, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Most monoclonal antibodies in oncology are administered in body–size‐based dosing schedules. This is believed to correct for variability in both drug distribution and elimination between patients. ...However, monoclonal antibodies typically distribute to the blood plasma and extracellular fluids only, which increase less than proportionally with the increase in body weight. Elimination takes place via proteolytic catabolism, a nonspecific immunoglobulin G elimination pathway, and intracellular degradation after binding to the target. The latter is the primary route of elimination and is related to target expression levels rather than body size. Taken together, the minor effects of body size on distribution and elimination of monoclonal antibodies and their usually wide therapeutic window do not support body–size‐based dosing. We evaluated effects of body weight on volume of distribution and clearance of monoclonal antibodies in oncology and show that a fixed dose for most of these drugs is justified based on pharmacokinetics. A survey of the savings after fixed dosing of monoclonal antibodies at our hospital showed that fixed dosing can reduce costs of health care, especially when pooling of preparations is not possible (which is often the case in smaller hospitals). In conclusion, based on pharmacokinetic parameters of monoclonal antibodies, there is a rationale for fixed dosing of these drugs in oncology. Therefore, we believe that fixed dosing is justified and can improve efficiency of the compounding. Moreover, drug spillage can be reduced and medication errors may become less likely.
Implications for Practice
The currently available knowledge of elimination of monoclonal antibodies combined with the publicly available data from clinical trials and extensive population pharmacokinetic (PopPK) modeling justifies fixed dosing. Interpatient variation in exposure is comparable after body weight and fixed dosing and most monoclonal antibodies show relatively flat dose‐response relationships. For monoclonal antibodies, this results in wide therapeutic windows and no reduced clinical efficacy after fixed dosing. Therefore, we believe that fixed dosing at a well‐selected dose can increase medication safety and help in reduction of costs of health care without the loss of efficacy or safety margins.
In the field of oncology, most drugs are administered in a body–size‐based dosing schedule instead of a fixed dose for all patients. This article presents the advantages of fixed dosing of monoclonal antibodies, arguing in favor of fixed dosing schemes for all currently approved antibodies in oncology.
Prostate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal ...locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29-47%.
LuLu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of
LuLu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields.
The PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic
LuLu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding
LuLu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle
LuLu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of
LuLu-PSMA-617.
This is the first prospective study to combine EBRT and ADT with
LuLu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of
LuLu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments.
ClinicalTrials, NCT05162573 . Registered 7 October 2021.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ATP-binding cassette (ABC) transporters are transmembrane efflux transporters that mediate cellular extrusion of a broad range of substrates ranging from amino acids, lipids, and ions to xenobiotics ...including many anticancer drugs. ABCB1 (P-GP) and ABCG2 (BCRP) are the most extensively studied apical ABC drug efflux transporters. They are highly expressed in apical membranes of many pharmacokinetically relevant tissues such as epithelial cells of the small intestine and endothelial cells of the blood capillaries in brain and testis, and in the placental maternal-fetal barrier. In these tissues, they have a protective function as they efflux their substrates back to the intestinal lumen or blood and thus restrict the intestinal uptake and tissue disposition of many compounds. This presents a major challenge for the use of many (anticancer) drugs, as most currently used anticancer drugs are substrates of these transporters. Herein, we review the latest findings on the role of apical ABC transporters in the disposition of anticancer drugs. We discuss that many new, rationally designed anticancer drugs are substrates of these transporters and that their oral availability and/or brain disposition are affected by this interaction. We also summarize studies that investigate the improvement of oral availability and brain disposition of many cytotoxic (e.g., taxanes) and rationally designed (e.g., tyrosine kinase inhibitor) anticancer drugs, using chemical inhibitors of these transporters. These findings provide a better understanding of the importance of apical ABC transporters in chemotherapy and may therefore advance translation of promising preclinical insights and approaches to clinical studies.
The DROP-IN gamma probe facilitates minimally invasive, robot-assisted prostate-specific membrane antigen–targeted radioguided surgery in patients with recurrent prostate cancer. This procedure holds ...promise for improving the intraoperative identification and removal of prostate cancer lesions.
It has been proven that intraoperative prostate-specific membrane antigen (PSMA)-targeted radioguidance is valuable for the detection of prostate cancer (PCa) lesions during open surgery. Rapid extension of robot-assisted, minimally invasive surgery has increased the need to make PSMA-radioguided surgery (RGS) robot-compliant.
To evaluate whether the miniaturized DROP-IN gamma probe facilitates translation of PSMA-RGS to robotic surgery in men with recurrent PCa.
This prospective feasibility study included 20 patients with up to three pelvic PCa recurrences (nodal or local) on staging PSMA positron emission tomography (PET) after previous curative-intent therapy.
Robot-assisted PSMA-RGS using the DROP-IN gamma probe was carried out 19–23 h after intravenous injection of 99mtechnetium PSMA-Investigation & Surgery (99mTc-PSMA-I&S).
The primary endpoint was the feasibility of robot-assisted PSMA-RGS. Secondary endpoints were a comparison of the radioactive status (positive or negative) of resected specimens and final histopathology results, prostate-specific antigen (PSA) response following PSMA-RGS, and complications according to the Clavien-Dindo classification.
Using the DROP-IN probe, 19/21 (90%) PSMA-avid lesions could be resected robotically. On a per-lesion basis, the sensitivity and specificity of robot-assisted PSMA-RGS was 86% and 100%, respectively. A prostate-specific antigen (PSA) reduction of >50% and a complete biochemical response (PSA <0.2 ng/ml) were seen in 12/18 (67%) and 4/18 (22%) patients, respectively. During follow-up of up to 15 mo, 4/18 patients (22%) remained free of biochemical recurrence (PSA ≤0.2 ng/ml). One patient suffered from a Clavien-Dindo grade >III complication.
The DROP-IN probe helps in realizing robot-assisted PSMA-RGS. The procedure is technically feasible for intraoperative detection of nodal or local PSMA-avid PCa recurrences.
A device called the DROP-IN probe facilitates minimally invasive, robot-assisted surgery guided by radioactive tracers in patients with recurrent prostate cancer. This procedure holds promise for improving the intraoperative identification and removal of prostate cancer lesions.
Background
Folate intake might reduce
68
GaGa-PSMA-11 uptake in tissues due to a competitive binding to the PSMA receptor. For diagnostic imaging, this could impact decision making, while during ...radioligand therapy this could affect treatment efficacy. The relationship between folate dose, timing of dosing and tumor and organ uptake is not well established. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict the effect of folates on
68
GaGa-PSMA-11 PET/CT uptake in salivary glands, kidneys and tumors.
Methods
A PBPK model was developed for
68
GaGa-PSMA-11 and folates (folic acid and its metabolite 5-MTHF), with compartments added that represent salivary glands and tumor. Reactions describing receptor binding, internalization and intracellular degradation were included. Model evaluation for
68
GaGa-PSMA-11 was performed by using patient scan data from two different studies (static and dynamic), while for folates data from the literature were used for evaluation. Simulations were performed to assess the effect of different folate doses (150 µg, 400 µg, 5 mg and 10 mg) on accumulation in salivary glands, kidney and tumor, also for patients with different tumor volumes (10, 100, 500 and 1000 mL).
Results
Final model evaluation showed that predictions adequately described data for both
68
GaGa-PSMA-11 and folates. Predictions of a 5-MTFH dose of 150 µg and folic acid dose of 400 µg (in case of administration at the same time as
68
GaGa-PSMA-11 (
t
= 0)) showed no clinically relevant effect on salivary glands and kidney uptake. However, the effect of a decrease in salivary glands and kidney uptake was determined to be clinically relevant for doses of 5 mg (34% decrease for salivary glands and 32% decrease for kidney) and 10 mg (36% decrease for salivary glands and 34% decrease for kidney). Predictions showed that tumor uptake was not relevantly affected by the co-administration of folate for all different folate doses (range 150 µg–10 mg). Lastly, different tumor volumes did not impact the folate effect on
68
GaGa-PSMA-11 biodistribution.
Conclusion
Using a PBPK model approach, high doses of folate (5 and 10 mg) were predicted to show a decrease of
68
GaGa-PSMA-11 salivary glands and kidney uptake, while intake by means of folate containing food or vitamin supplements showed no relevant effects. In addition, tumor uptake was not affected by folate administration in the simulated dose ranges (150 µg–10 mg). Differences in tumor volume are not expected to impact folate effects on
68
GaGa-PSMA-11 organ uptake.
Objective
To investigate whether combination treatment of prostate‐specific membrane antigen (PSMA)‐based radioguided surgery (RGS) with short‐term androgen deprivation therapy (ADT) improves ...oncological outcomes in men with oligorecurrent prostate cancer (PCa) as compared to treatment with short‐term ADT only.
Methods
The TRACE‐II study is an investigator‐initiated, prospective, randomised controlled clinical trial. Patients (aged >18 years) with hormone‐sensitive recurrent PCa after radical prostatectomy or radiotherapy (brachytherapy or external beam radiotherapy), with involvement of ≤2 lymph nodes or local oligorecurrent disease within the pelvis as determined by PSMA positron emission tomography (PET)/computed tomography (CT) are randomly assigned in a 1:1 ratio between 6‐month ADT (Arm A) or 6‐month ADT plus RGS (Arm B). The primary objective is to determine clinical progression‐free survival (CPFS) at 24 months. After PSMA‐RGS, CPFS is defined as the time between the start of treatment and the appearance of a re‐recurrence (any N1 or M1) as suggested by PSMA‐PET/CT or symptoms related to progressive PCa, or death from any cause. The secondary objectives include metastasis‐free survival at 2, 5 and 10 years, biochemical progression‐free survival at 2 years, and patient‐reported quality of life at 2, 5 and 10 years. A total of 60 patients, 30 per arm, will be included. The trial is powered (80%) to detect at least a 30% absolute difference in CPFS between the two study arms in the period 2 years after randomisation. We expect to enrol the required participants in 3 years. The study has an expected duration of 5 years in total.
Conclusions
Combining RGS with short‐term ADT might be oncologically beneficial for patients with oligorecurrent PCa. In this first randomised controlled trial, we are investigating the potential oncological benefits of this combined treatment, while also focusing on maintaining quality of life.
Background
Radiopharmaceuticals are considered as regular medicinal products and therefore the same regulations as for non-radioactive medicinal products apply. However, specific aspects should be ...considered due to the radiochemical properties. Radiopharmaceutical dedicated monographs are developed in the European Pharmacopoeia to address this. Currently, different quality control methods for non-registered radiopharmaceuticals are utilized, often focusing on radio-TLC only, which has its limitations. When the radiochemical yield (RCY) is measured by radio-TLC analysis, degradation products caused by radiolysis are frequently not detected. In contrast, HPLC analysis defines the radiochemical purity (RCP), allowing for detection of peak formation related to radiolysis. During the introduction and optimization phase of therapeutic radiopharmaceuticals, significant percentages of impurities, like radiolysed construct formation, may have consequential impact on patient treatment. Since more hospitals and institutes are offering radiopharmaceutical therapies, such as
177
LuLu-PSMA with an in-house production, the demand for adequate quality control is increasing. Here we show the optimization and implementation of a therapeutic radiopharmaceutical, including the comparison of ITLC and HPLC quality control.
Results
Downscaled conditions (74 MBq/μg) were in concordance to clinical conditions (18 GBq/250 µg, 5 mL syringe/100 mL flacon); all results were consistent with an > 98% RCY (radio-TLC) and stability of > 95% RCP (HPLC). Radio-TLC did not identify radiolysis peaks, while clear identification was performed by HPLC analysis. Decreasing the RCP with 50%, reduced the cell-binding capacity with 27%.
Conclusion
This research underlines the importance of the radiolabeling and optimization including clinical implementation and clarifies the need for cross-validation of the RCY and RCP for quality control measurements. Only HPLC analysis is suitable for identification of radiolysis. Here we have proven that radiolysed
177
LuLu-PSMA has less binding affinity and thus likely will influence treatment efficacy. HPLC analysis is therefore essential to include in at least the validation phase of radiopharmaceutical implementation to ensure clinical treatment quality.
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