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Cureus Sep 2023Leptomeningeal carcinomatosis (LC) is an uncommon sequelae of metastatic cancer affecting the pia and arachnoid mater. It has been postulated that recent improvements...
Leptomeningeal carcinomatosis (LC) is an uncommon sequelae of metastatic cancer affecting the pia and arachnoid mater. It has been postulated that recent improvements in cancer patient survival time have increased the frequency of LC and other rare metastatic conditions that patients previously would not have lived long enough to experience. LC carries a universally poor prognosis with a mean survival of between two to four months if treated; however, the recent increase in incidence has allowed for further research into the condition and potential treatments. Options for administering chemotherapy have been limited in the past, but recent developments in surgical chemotherapeutic ports have allowed for intrathecal delivery of drugs like methotrexate without systemic exposure. In fact, innovative delivery systems undergoing clinical trials can deliver these drugs in a metronomic fashion to limit the leukoencephalopathy complications of methotrexate. Primary breast cancer is the most common source of metastatic leptomeningeal lesions, and such a lesion was observed by the authors in the cadaver of a 70-year-old Caucasian female with unspecified breast cancer in a medical school anatomic laboratory. The cause of death was listed as "complication of malignant neoplasm of unspecified site of unspecified female breast." Through this case report, we seek to develop our understanding of this rare metastatic phenomenon and highlight the importance of student cadaveric dissection.
PubMed: 37790014
DOI: 10.7759/cureus.44533 -
Paediatric Drugs Jul 2024To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF).
BACKGROUND
To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF).
OBJECTIVE
This study assessed the penetration of bevacizumab, as part of a metronomic antiangiogenic treatment regimen, into the CSF of children, adolescents, and young adults with recurrent brain tumors.
PATIENTS AND METHODS
Serum and CSF concentrations, malignant cells, and vascular endothelial growth factor A (VEGF-A) were analyzed in 12 patients (5-27 years) following 10 mg/kg bevacizumab intravenous biweekly administration (EudraCT number 2009-013024-23). A population pharmacokinetic model including body weight, albumin, and tumor type as influential factors was extended to quantify the CSF penetration of bevacizumab.
RESULTS
Apart from in serum (minimum concentration/maximum concentration [C/C] 77.0-305/267-612 mg/L, median 144/417 mg/L), bevacizumab could be quantified in the CSF (0.01-2.26 mg/L, median 0.35 mg/L). The CSF/serum ratio was 0.16 and highly variable between patients. Malignant cells could be detected in CSF before initiation of treatment in five of 12 patients; after treatment, the CSF was cleared in all patients. VEGF-A was detected in three patients before treatment (mean ± SD: 20 ± 11 pg/mL), and was still measurable in one of these patients despite treatment (16 pg/mL).
CONCLUSIONS
This pharmacokinetic pilot study indicated penetration of bevacizumab into the CSF in a population of children, adolescents, and young adults with recurrent brain tumors.
Topics: Humans; Bevacizumab; Child; Adolescent; Brain Neoplasms; Male; Female; Child, Preschool; Adult; Young Adult; Neoplasm Recurrence, Local; Angiogenesis Inhibitors; Vascular Endothelial Growth Factor A; Antineoplastic Agents, Immunological
PubMed: 38587585
DOI: 10.1007/s40272-024-00624-y -
ESMO Open May 2024There is no consensus on the second-line treatment of patients with progressive high-grade neuroendocrine neoplasms (NENs G3) and large-cell lung neuroendocrine...
A new schedule of one week on/one week off temozolomide as second-line treatment of advanced neuroendocrine carcinomas (TENEC-TRIAL): a multicenter, open-label, single-arm, phase II trial.
BACKGROUND
There is no consensus on the second-line treatment of patients with progressive high-grade neuroendocrine neoplasms (NENs G3) and large-cell lung neuroendocrine carcinoma. These patients generally have poor performance status and low tolerance to combination therapy. In this trial, we aim to evaluate the efficacy and safety of temozolomide given every other week in patients with advanced platinum-pretreated NENs G3.
PATIENTS AND METHODS
This trial is an open-label, non-randomized, phase II trial. Patients with platinum-pretreated metastatic neuroendocrine carcinoma were treated with 75 mg/m/day of temozolomide for 7 days, followed by 7 days of no treatment (regimen one week on/one week off). The primary endpoint was the overall response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and tolerability. This study is registered with ClinicalTrials.gov, NCT04122911.
RESULTS
From 2017 to 2020, 38 patients were enrolled. Among the patients with determined Ki67, 12 out of 36 (33.3%) had a Ki67 index <55% and the remaining 24 out of 36 (66.6%) had an index ≥55%. Overall response rate was 18% (7/38), including one complete response and six partial responses. The median PFS was 5.86 months [95% confidence interval (CI) 4.8 months-not applicable) and the median OS was 12.1 months (95% CI 5.6-20.4 months). The 1-year PFS rate was 37%. No statistically significant difference in median PFS [hazard ratio 1.3 (95% CI 0.6-2.8); P = 0.44] and median OS [hazard ratio 1.1 (95% CI 0.5-2.4); P = 0.77] was observed among patients with Ki67 <55% versus ≥55%. Only G1-G2 adverse events were registered, the most common being G1 nausea, diarrhea and abdominal pain.
CONCLUSION
One week on/one week off temozolomide shows promising activity in patients with poorly differentiated NEN. The good safety profile confirmed the possibility of using this scheme in patients with poor performance status.
Topics: Humans; Male; Temozolomide; Female; Middle Aged; Carcinoma, Neuroendocrine; Aged; Adult; Antineoplastic Agents, Alkylating; Drug Administration Schedule; Lung Neoplasms; Progression-Free Survival
PubMed: 38615472
DOI: 10.1016/j.esmoop.2024.103003 -
NPJ Systems Biology and Applications Feb 2024Despite the revolutionary impact of immune checkpoint inhibition on cancer therapy, the lack of response in a subset of patients, as well as the emergence of resistance,...
Despite the revolutionary impact of immune checkpoint inhibition on cancer therapy, the lack of response in a subset of patients, as well as the emergence of resistance, remain significant challenges. Here we explore the theoretical consequences of the existence of multiple states of immune cell exhaustion on response to checkpoint inhibition therapy. In particular, we consider the emerging understanding that T cells can exist in various states: fully functioning cytotoxic cells, reversibly exhausted cells with minimal cytotoxicity, and terminally exhausted cells. We hypothesize that inflammation augmented by drug activity triggers transitions between these phenotypes, which can lead to non-genetic resistance to checkpoint inhibitors. We introduce a conceptual mathematical model, coupled with a standard 2-compartment pharmacometric (PK) model, that incorporates these mechanisms. Simulations of the model reveal that, within this framework, the emergence of resistance to checkpoint inhibitors can be mitigated through altering the dose and the frequency of administration. Our analysis also reveals that standard PK metrics do not correlate with treatment outcome. However, we do find that levels of inflammation that we assume trigger the transition from the reversibly to terminally exhausted states play a critical role in therapeutic outcome. A simulation of a population that has different values of this transition threshold reveals that while the standard high-dose, low-frequency dosing strategy can be an effective therapeutic design for some, it is likely to fail a significant fraction of the population. Conversely, a metronomic-like strategy that distributes a fixed amount of drug over many doses given close together is predicted to be effective across the entire simulated population, even at a relatively low cumulative drug dose. We also demonstrate that these predictions hold if the transitions between different states of immune cell exhaustion are triggered by prolonged antigen exposure, an alternative mechanism that has been implicated in this process. Our theoretical analyses demonstrate the potential of mitigating resistance to checkpoint inhibitors via dose modulation.
Topics: Humans; Immune System Exhaustion; Inflammation
PubMed: 38336968
DOI: 10.1038/s41540-024-00336-6 -
Heliyon Jan 2024Epidermal growth factor receptor (EGFR) mutations have been identified as promising therapeutic targets for non-small cell lung cancer. Osimertinib, a third-generation...
An epidermal growth factor receptor-mutated lung adenocarcinoma patient with brain lesions resisted to osimertinib monotherapy but achieved more than 4 years of survival in osimertinib plus bevacizumab metronomic treatment.
BACKGROUND
Epidermal growth factor receptor (EGFR) mutations have been identified as promising therapeutic targets for non-small cell lung cancer. Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor-targeting drug, has good anti-tumor ability and excellent intracranial effects. However, management of osimertinib resistance is a clinical challenge. The clinical benefit of osimertinib combined with the antiangiogenic drug, bevacizumab, remains to be determined.
CASE PRESENTATION
A 40-year-old female with right lung adenocarcinoma (cT2aN3M1c, IVb) was confirmed positive for EGFR exon 19 deletion mutation (c.2235_2249del, 1.3%). After receiving 5 months of osimertinib (80 mg, qd) therapy, the patient's disease progressed and she subsequently accepted treatment with osimertinib (80 mg, qd) plus bevacizumab (15 mg/kg, q21d) and achieved notable clinical remission for 23 months until renal impairment occurred, after which bevacizumab was discontinued. The patient had 6 months of remission before progression, after which bevacizumab was added again. To date, the disease has been under control. The brain lesion showed partial response again, and the side effects of bevacizumab were tolerable. The overall survival time exceeded 4 years.
CONCLUSION
This case report describes a treatment strategy for osimertinib-resistant patients with EGFR exon 19 deletion mutations. Metronomic treatment with osimertinib plus bevacizumab was achieved for more than 4 years.
PubMed: 38298673
DOI: 10.1016/j.heliyon.2024.e24378