Chemotherapy最新文献

Background: Despite major advances in cancer treatment in the past years, there is a need to optimize chemotherapeutic drug dosing strategies to reduce toxicities, suboptimal responses, and the risk of relapse. Most cancer drugs have a narrow therapeutic index with substantial pharmacokinetics variability. Yet, current dosing approaches do not fully account for the complex pathophysiological characteristics of the patients. In this regard, the effect of sex on anticancer chemotherapeutic drugs' disposition is still underexplored. In this article, we review sex differences in chemotherapeutic drug pharmacokinetics; we suggest a novel approach that integrates sex into the traditional a priori body surface area (BSA) dosing selection model, and finally, we provide an overview of the potential benefits of a broader use of therapeutic drug monitoring (TDM) in oncology.

Summary: To date, anticancer chemotherapeutic drug dosing is most often determined by BSA, a method widely used for its ease of practice, despite criticism for not accounting for individual factors, notably sex. Anatomical, physiological, and biological differences between males and females can affect pharmacokinetics, including drug metabolism and clearance. At equivalent doses, females tend to display higher circulating exposure and more organ toxicities, which has been formally demonstrated at present for about 20% of chemotherapeutic drugs. An alternative could be the sex-adjusted BSA (SABSA), incorporating a 10% increase in dosing for males and a 10% decrease for females, though this approach still lacks formal clinical validation. Another strategy to reduce treatment-related toxicity and potentially enhance clinical outcomes could be a more widespread use of TDM, for which a benefit has been demonstrated for 5-fluorouracil, busulfan, methotrexate, or thiopurines.

Key messages: The inclusion of sex besides BSA in an easy-to-implement formula such as SABSA could improve a priori chemotherapy dosing selection, even though it still requires clinical validation. The a posteriori use of TDM could further enhance treatment efficacy and safety in oncology.

Introduction: We report the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of a multi-kinase inhibitor (TG02 capsule) as a new therapy for patients with recurrent high-grade gliomas in China.

Methods: This is a single-center, dose-escalation, open-label phase I study, which enrolled patients with recurrent high-grade gliomas who failed to temozolomide. Patients were assigned sequentially into different dose groups and received TG02 every 4 weeks. The dose was increased in a traditional 3 + 3 design. Primary endpoints were the dose-limited toxicity (DLT) and the maximum tolerated dose (MTD).

Results: Twelve patients (8 glioblastomas, 4 diffuse astrocytoma) were enrolled between May 2019 and November 2021. Three patients received 100 mg and 9 received 150 mg TG02 twice a week. The plasma concentration of TG02 reached the maximum at 2 h after administration, and the elimination half-life was about 7 h. No DLT occurred and MTD was not defined in this study. Eleven patients had one or more investigator-assessed treatment-related adverse events (TRAEs). The most frequent TRAEs were vomiting (91.7%) and diarrhea (75.0%), and 50% of the patients had grade 3 or 4 adverse events. There were no treatment-related deaths. The median progression-free survival and overall survival were 1.77 (95% confidence interval [CI]: 0.82-4.24) and 9.63 (95% CI: 2.66-not estimated) months, respectively.

Conclusions: TG02 capsule 150 mg twice a week is safe and tolerable in Chinese patients with recurrent high-grade gliomas. Patients who failed to temozolomide showed obvious tumor reduction when switching to TG02 capsule. The efficacy of recurrent gliomas warrants further investigation.

Background: Targeted therapies have revolutionized the treatment of hematological malignancies, offering improved efficacy with fewer off-target effects compared to traditional chemotherapy. However, significant pharmacokinetic (PK) and pharmacodynamic (PD) variability exists among patients receiving these therapies.

Summary: Therapeutic drug monitoring (TDM) measures drug exposure and thereby helps to adjust the dose of a drug to maintain its concentration within a target range. It is frequently applied for drugs with characteristics like PK variability or narrow therapeutic window, among others, to ensure optimal therapeutic outcome while minimizing adverse effects. Many molecular targeted agents (MTAs) for malignancies, especially tyrosine kinase inhibitors, exhibit significant variability in exposure, and yet are still dosed with a "one-size-fits-all" approach. While this is partially culprit to regulatory approval requirements of MTA, it contradicts principles of targeted therapy. PK/PD variability necessitates a personalized approach to dosing in order to optimize therapeutic outcomes and minimize toxicity. TDM provides an avenue to refine dosing strategies based on individual patient characteristics.

Key messages: Through incorporation of TDM, treatment of hematological malignancies could move toward target concentration-driven dosing in clinical trials and regulatory frameworks. Establishing target concentrations for MTA requires solid exposure-response and exposure-toxicity analyses in the population of interest. To establish such reference ranges, large populational analyses are necessitated, underlining the importance of the incorporation of such endpoints into phase III trials. Economic restrictions, sample transportation logistics, turnaround times, and interpretation may hinder the application of a TDM-guided dosing approach in routine care. Ultimately, personalized TDM-guided dosing could improve patient outcomes and quality of life through minimizing toxicity.

Background: Hepatocellular carcinoma (HCC) is one of the primary types of liver cancer, and the mortality trend of HCC patients is estimated to continue rising in the future. Chemotherapy drugs or targeted therapies are considered primary treatment modalities for intermediate-stage or advanced-stage HCC. Although these drugs can extend the survival rate of HCC patients, prolonged treatment often raises concerns about drug resistance or cancer recurrence, leading to undesirable therapeutic outcomes. Drug treatments generally involve promoting cytotoxicity and inhibiting oncogenic signaling pathways, and the response of cancer cells to drug-induced stress situations may potentially impact the effectiveness of treatment. The unfolded protein response (UPR) acts as a cellular stress response mechanism, activating pathways such as DNA repair and autophagy to help cellular survival when cells are damaged. It has also been shown that under sustained or excessive stress, UPR can control cell fate toward programmed cell death, such as apoptosis. Previous studies have found that activation of UPR plays an essential role in cancer cell growth and drug resistance. Various molecules or signaling pathways regulated by the UPR assist cancer cells in responding to anticancer drugs, enabling their survival during treatment.

Summary: The present review illustrated genetic molecules or signaling pathways controlled by the UPR and investigates their influence on liver cancer drugs. Moreover, the review also summarizes the partial effects of UPR, including lipid droplet formation and inflammatory stimulation, and their roles in HCC development and drug resistance, respectively.

Key message: Unraveling and targeting ER stress provide potential therapeutic strategies for HCC treatment.

Introduction: Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has shown significant clinical benefits in patients with EGFR-sensitizing mutations or the EGFR T790M mutation. The homologous recombination (HR) pathway is crucial for repairing DNA double-strand breaks (DSBs). Rad51 plays a central role in HR, facilitating the search for homology and promoting DNA strand exchange between homologous DNA molecules. Rad51 is overexpressed in numerous types of cancer cells. B02, a specific small molecule inhibitor of Rad51, inhibits the DNA strand exchange activity of Rad51. Previous studies have indicated that B02 disrupted Rad51 foci formation in response to DNA damage and inhibited DSBs repair in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo. However, the potential therapeutic effects of combining osimertinib with a Rad51 inhibitor are not well understood. The aim of this study was to elucidate whether the downregulation of Rad51 expression and activity can enhance the osimertinib-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells.

Methods: We used the MTS, trypan blue dye exclusion and colony-formation ability assay to determine whether osimertinib alone or in combination with B02 had cytotoxic effects on NSCLC cell lines. Real-time polymerase chain reaction was conducted to measure the amounts of Rad51 mRNA. The protein levels of phosphorylated AKT and Rad51 were determined by Western blot analysis.

Results: We found that osimertinib reduced Rad51 expression by inactivating AKT activity. Rad51 knockdown using small interfering RNA or AKT inactivation through the phosphatidylinositol 3-kinase inhibitor LY294002 or si-AKT RNA transfection enhanced the cytotoxic and growth inhibitory effects of osimertinib. In contrast, AKT-CA (a constitutively active form of AKT) vector-enforced expression could mitigate the cytotoxic and cell growth inhibitory effects of osimertinib. Furthermore, B02 significantly enhanced the cytotoxic and cell growth inhibitory effects of osimertinib in NSCLC cells. Compared to parental cells, the activation of AKT and Rad51 expression in osimertinib-resistant cells could not be significantly inhibited by osimertinib treatment. Moreover, the increased expression of Rad51 is associated with the resistance mechanism in osimertinib-resistant H1975 and A549 cells.

Conclusion: Collectively, the downregulation of Rad51 expression and activity enhances the cytotoxic effect of osimertinib in human NSCLC cells.

Introduction: Therapeutic drug monitoring of imatinib is widely performed to individualize imatinib dosage. While N-desmethyl imatinib is an active metabolite of imatinib, its concentrations are not routinely determined.

Methods: Imatinib and N-desmethyl imatinib trough plasma concentrations at steady-state were obtained from 295 patients with either chronic myeloid leukemia or gastrointestinal stromal tumor to see whether N-desmethyl imatinib provided additional information. Pharmacokinetic data were analyzed using a nonlinear mixed effect approach. Correlations between several pharmacokinetic metrics of drug exposure were evaluated.

Results: The mean value of the N-desmethyl imatinib/imatinib ratio of trough concentrations was 0.31 with half of the values between 0.23 and 0.37. N-desmethyl imatinib and total (i.e., N-desmethyl imatinib plus imatinib) trough plasma concentrations or area under the curve values were closely correlated with imatinib values. The distribution of imatinib or total concentrations between patients requiring imatinib dosage adjustment, or not, was similar.

Conclusion: These results do not clearly support routine N-desmethyl monitoring since it does not provide additional information to imatinib data.

Introduction: Duodenal squamous cell carcinoma is an exceedingly rare occurrence among gastrointestinal malignancies, and its diagnosis and treatment are not well understood.

Case presentation: In this report, we present a case of duodenal squamous cell carcinoma with liver and adrenal metastasis. The patient was treated with gemcitabine and S-1, achieving a progression-free survival of 7 months and an overall survival of 9 months. Additionally, we review the features and treatment approaches reported in previous cases of primary duodenal carcinoma.

Conclusion: Clearly, further case reports, such as ours, can contribute to a deeper understanding that is essential for characterizing this entity and establishing management guidelines.

Introduction: Nocardia spp. is an opportunistic pathogen capable of causing localized and disseminated infections in immunocompromised hosts. It is critical for serious infections to have an early and accurate identification of this pathogen in order to enable timely and focused combination antimicrobial treatment.

Case presentation: We describe the case of an 87-year-old patient previously treated for myasthenia gravis with corticosteroids and azathioprine. Patient was admitted at the emergency department with clinical signs of sepsis with cellulitis of right hand associated with injury acquired after gardening and trimming roses and did not respond to empirical antimicrobial treatment. Computerized tomography revealed pulmonary infiltrates with inflammatory etiology. Nocardia cyriacigeorgica was cultivated from blood culture, skin swab, abscess aspirate, and endotracheal aspirate and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), 16S rRNA sequencing, and whole genome sequencing (WGS). Susceptibility testing was performed with E-test (bioMerieux, Marcy-l'Étoile, France), and corresponding resistance genes were detected by WGS. Resistance to amoxicillin-clavulanate, azithromycin, ciprofloxacin, and vancomycin was detected by both methods. Despite all interventions and the patient receiving antimicrobial treatment including imipenem-cilastatin, amikacin, and trimethoprim-sulfamethoxazole, the course and outcome of infection were unfavorable.

Conclusion: We would like to emphasize the need to consider the possibility of disseminated Nocardia infection in immunocompromised patients, especially in patients receiving long-term corticosteroid treatment with skin infections and/or cavitary lung lesions, especially if these do not improve with standard antimicrobial treatment. Precise species identity provides a critical guide for physicians in the choice of targeted treatment. Thanks to MALDI-TOF MS, Nocardia spp. identification is now available in routine lab work. WGS is still inevitable for the identification of uncommon and novel species due to the high sequence similarities between closely related species and the genetic diversity of that genus.

Introduction: High-dose methotrexate (MTX) is used to treat pediatric acute lymphoblastic leukemia (ALL). The drug has a low therapeutic index and a highly interindividual variability in systemic exposure. These characteristics necessitate dose adjustments and therapeutic drug monitoring protocols, while population pharmacokinetic (POP/PK) models may enable more precise drug dosing. Therefore, we assessed the performance of external POP/PK models in ALL children receiving high-dose MTX.

Methods: We retrospectively harvested clinical and laboratory data from ALL children during their first two cycles of chemotherapy. A POP/PK model was elaborated using the Monolix suite 2024R1. External models were selected from PUBMED based on strict inclusion/exclusion criteria, and their fit to the actual data was assessed by calculating bias (percentage prediction error [PE%]) and precision (percentage root mean squared error [RMSE%]).

Results: Thirty-seven ALL children participated in the study (18 males, median age 5.1 years, range 1.7-15.2 years), and six external POP/PK models were chosen. Except for one model (median PE% value, -97.45%), all models exhibited acceptable bias (median PE% values, -4.17%-2.67%), despite none of them demonstrating good precision (median RMSE% values, 89.19%-120.40%).

Conclusion: External models should be accurately evaluated before they are implemented in clinical practice, even when patients share very similar characteristics.