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The Oncologist Sep 2023There is limited real-world evidence on how increasing use of treatment intensification in metastatic castration-sensitive prostate cancer (mCSPC) has influenced...
BACKGROUND
There is limited real-world evidence on how increasing use of treatment intensification in metastatic castration-sensitive prostate cancer (mCSPC) has influenced treatment decisions in metastatic castration-resistant prostate cancer (mCRPC). The study objective was to evaluate the impact of novel hormonal therapy (NHT) and docetaxel use in mCSPC on first-line treatment patterns among patients with mCRPC in 5 European countries and the United States (US).
METHODS
Physician-reported data on patients with mCRPC from the Adelphi Prostate Cancer Disease Specific Program were descriptively analyzed.
RESULTS
A total of 215 physicians provided data on 722 patients with mCRPC. Across 5 European countries and the US, 65% and 75% of patients, respectively, received NHT, and 28% and 9% of patients, respectively, received taxane chemotherapy as first-line mCRPC treatment. In Europe, patients who had received NHT in mCSPC (n = 76) mostly received taxane chemotherapy in mCRPC (55%). Patients who had received taxane chemotherapy, or who did not receive taxane chemotherapy or NHT in mCSPC (n = 98 and 434, respectively) mostly received NHT in mCRPC (62% and 73%, respectively). In the US, patients who had received NHT, taxane chemotherapy, or neither in mCSPC (n = 32, 12, and 72, respectively) mostly received NHT in mCRPC (53%, 83%, and 83%, respectively). Two patients in Europe were rechallenged with the same NHT.
CONCLUSIONS
These findings suggest that physicians consider mCSPC treatment history when making first-line treatment decisions in mCRPC. Further studies are needed to better understand optimal treatment sequencing, especially as new treatments emerge.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Docetaxel; Taxoids; Androgen Antagonists; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Retrospective Studies
PubMed: 37014097
DOI: 10.1093/oncolo/oyad046 -
Medicine Dec 2023The cost-effectiveness of sotorasib and its reasonable price in the United States (US) and China remain unknown. Our objective was to estimate the price at which...
Sotorasib versus Docetaxel for treatment of US and Chinese patients with advanced non-small-cell lung cancer with KRAS p.G12C-mutated: A cost-effectiveness analysis to inform drug pricing.
BACKGROUND
The cost-effectiveness of sotorasib and its reasonable price in the United States (US) and China remain unknown. Our objective was to estimate the price at which sotorasib could be economical as second-line treatment for advanced non-small-cell lung cancer patients with Kirsten rat sarcoma viral oncogene homolog p.G12C-mutation in 2 countries.
METHODS
We conducted an economic evaluation from the perspective of US and Chinese payers. To analyze US patients, we built a partitioned survival model. However, since we lacked Asian-specific overall survival data, we created a state transition model for the Chinese patients. We obtained patients' baseline characteristics and clinical data from CodeBreaK200, while utilities and costs were gathered from public databases and published literature. We calculated costs (US dollar), life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. We conducted price simulation to guide pricing strategies. Additionally, we assessed the reliability of our results through sensitivity analyses, scenario analyses, and subgroup analyses.
RESULTS
The incremental cost-effectiveness ratios of sotorasib compared to docetaxel were $1501,852 per quality-adjusted life-years (QALY) in the US and $469,106/QALY in China, respectively, which meant sotorasib was unlikely to be economical at the currently available price of $20,878 (240 × 120 mg) in both countries. Price simulation results revealed that sotorasib would be preferred at a price lower than $1400 at the willingness-to-pay threshold of $37,376 in China and a price lower than $2220 at the willingness-to-pay threshold of $150,000 in the US. Sensitivity, scenario, and subgroup analyses showed that these conclusions were generally robust, the model was most sensitive to the utilities of progression-free survival and post-progression survival.
CONCLUSIONS
Sotorasib could potentially be a cost-effective therapy in the US and China following price reductions. Our evidence-based pricing strategy can assist decision-makers and clinicians in making optimal decisions. However, further analysis of budget impact and affordability is needed.
Topics: Humans; United States; Docetaxel; Carcinoma, Non-Small-Cell Lung; Proto-Oncogene Proteins p21(ras); Cost-Effectiveness Analysis; Drug Costs; Reproducibility of Results; Lung Neoplasms; Cost-Benefit Analysis; Quality-Adjusted Life Years
PubMed: 38115313
DOI: 10.1097/MD.0000000000036387 -
BMC Cancer Nov 2023Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease....
BACKGROUND
Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated.
METHODS
Ibrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival [PFS] for CRC) in phase 2.
RESULTS
A total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9-7.5) months in RCC, 4.0 (2.7-4.2) months in GC, and 5.4 (4.1-5.8) months in CRC.
CONCLUSIONS
Clinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT02599324.
Topics: Humans; Carcinoma, Renal Cell; Piperidines; Adenine; Antineoplastic Combined Chemotherapy Protocols; Kidney Neoplasms
PubMed: 37919668
DOI: 10.1186/s12885-023-11539-1 -
Biomedicines Oct 2023Taxanes, particularly docetaxel (DTX), has been widely used for combination therapy of head and neck squamous cell carcinoma (HNSCC). For locally advanced unresectable... (Review)
Review
Taxanes, particularly docetaxel (DTX), has been widely used for combination therapy of head and neck squamous cell carcinoma (HNSCC). For locally advanced unresectable HNSCC, DTX combined with cisplatin and 5-fluorouracil as a revolutionary treatment revealed an advantage in the improvement of patient outcome. In addition, DTX plus immune check inhibitors (ICIs) showed low toxicity and an increased response of patients with recurrent or metastatic HNSCC (R/M HNSCC). Accumulated data indicate that taxanes not only function as antimitotics but also impair diverse oncogenic signalings, including angiogenesis, inflammatory response, ROS production, and apoptosis induction. However, despite an initial response, the development of resistance remains a major obstacle to treatment response. Taxane resistance could result from intrinsic mechanisms, such as enhanced DNA/RNA damage repair, increased drug efflux, and apoptosis inhibition, and extrinsic effects, such as angiogenesis and interactions between tumor cells and immune cells. This review provides an overview of taxanes therapy applied in different stages of HNSCC and describe the mechanisms of taxane resistance in HNSCC. Through a detailed understanding, the mechanisms of resistance may help in developing the potential therapeutic methods and the effective combination strategies to overcome drug resistance.
PubMed: 38001888
DOI: 10.3390/biomedicines11112887 -
European Urology Oncology May 2024Mutations in the speckle-type POZ (SPOP) gene are frequently identified in prostate cancer (PC); yet, prognostic implications for affected patients remain unclear.... (Review)
Review
CONTEXT
Mutations in the speckle-type POZ (SPOP) gene are frequently identified in prostate cancer (PC); yet, prognostic implications for affected patients remain unclear. Limited consensus exists regarding tailored treatments for SPOP-mutant (SPOPmut) PC.
OBJECTIVE
To elucidate the prognostic and predictive significance of SPOP mutations across distinct PC stages and treatments.
EVIDENCE ACQUISITION
A systematic literature search of PubMed, Embase, and Scopus was conducted up to January 29, 2024. The meta-analysis included studies comparing survival outcomes between SPOPmut and SPOP wild-type (SPOPwt) PC.
EVIDENCE SYNTHESIS
From 669 records, 26 studies (including five abstracts) were analyzed. A meta-analysis of metastasis-free survival in localized (hazard ratio [HR]: 0.72, 95% confidence interval [CI]: 0.59-0.88; p < 0.01) and overall survival (OS) in metastatic PC (HR: 0.64, 95% CI: 0.53-0.76; p < 0.01) showed a favorable prognosis for patients with SPOPmut PC. In metastatic settings, SPOP mutations correlated with improved progression-free survival (PFS) and OS in patients undergoing androgen deprivation therapy ± androgen receptor signaling inhibitor (HR: 0.51, 95% CI: 0.35-0.76, p < 0.01, and HR: 0.60, 95% CI:0.46-0.79, p < 0.01, respectively). In metastatic castration-resistant PC, only abiraterone provided improved PFS and OS to patients with SPOP mutations compared with patients with SPOPwt, but data were limited. SPOP mutations did not correlate with improved PFS (p = 0.80) or OS (p = 0.27) for docetaxel.
CONCLUSIONS
Patients with SPOPmut PC seem to exhibit superior oncological outcomes compared with patients with SPOPwt. Tailored risk stratification and treatment approaches should be explored in such patients.
PATIENT SUMMARY
Speckle-type POZ (SPOP) mutations could be a favorable prognostic factor in patients with prostate cancer (PC) and may also predict better progression-free and overall survival than treatment with hormonal agents. Therefore, less intensified treatments omitting chemotherapy for patients with SPOP-mutant PC should be explored in clinical trials.
PubMed: 38704358
DOI: 10.1016/j.euo.2024.04.011 -
Genetics Research 2023The role of disulfidptosis-related lncRNAs remains unclear in lung adenocarcinoma.
BACKGROUND
The role of disulfidptosis-related lncRNAs remains unclear in lung adenocarcinoma.
METHODS
Analysis in R software was conducted using different R packages, which are based on the public data from The Cancer Genome Atlas (TCGA) database. The transwell assay was used to evaluate the invasion and migration abilities of lung cancer cells.
RESULTS
In our study, we identified 1401 lncRNAs significantly correlated with disulfidptosis-related genes (|Cor| > 0.3 and < 0.05). Then, we constructed a prognosis model consisting of 11 disulfidptosis-related lncRNAs, including AL133445.2, AL442125.1, AC091132.2, AC090948.1, AC020765.2, CASC8, AL606834.1, LINC00707, OGFRP1, U91328.1, and GASAL1. This prognosis model has satisfactory prediction performance. Also, the risk score and clinical information were combined to develop a nomogram. Analyses of biological enrichment and immune-related data were used to identify underlying differences between patients at high-risk and low-risk groups. Moreover, we noticed that the immunotherapy nonresponders have higher risk scores. Meanwhile, patients at a high risk responded more strongly to docetaxel, paclitaxel, and vinblastine. Furthermore, further analysis of the model lncRNA OGFRP1 was conducted, including clinical, immune infiltration, biological enrichment analysis, and a transwell assay. We discovered that by inhibiting OGFRP1, the invasion and migration abilities of lung cancer cells could be remarkably hindered.
CONCLUSION
The results of our study can provide directions for future research in the relevant areas. Moreover, the prognosis signature we identified has the potential for clinical application.
Topics: Humans; RNA, Long Noncoding; Prognosis; Nomograms; Lung Neoplasms; Adenocarcinoma; Tumor Microenvironment
PubMed: 37575978
DOI: 10.1155/2023/6670514 -
Lung Cancer (Amsterdam, Netherlands) May 2024Given the modest efficacy of docetaxel in advanced non-small cell lung cancer (NSCLC), this study assesses the therapeutic potential and safety profile of anlotinib in... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Given the modest efficacy of docetaxel in advanced non-small cell lung cancer (NSCLC), this study assesses the therapeutic potential and safety profile of anlotinib in combination with docetaxel compared to docetaxel monotherapy as a second-line therapy for patients with advanced NSCLC.
MATERIALS AND METHODS
In this phase II study, patients with advanced NSCLC experiencing failure with first-line platinum-based regimens were randomized in a 1:1 ratio to receive either anlotinib plus docetaxel or docetaxel alone. Primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety as secondary endpoints.
RESULTS
A total of 83 patients were randomized. The combination of anlotinib and docetaxel significantly extended median PFS to 4.4 months compared to 1.6 months for docetaxel alone (hazard ratio [HR] = 0.38, 95 % confidence interval [CI]: 0.23-0.63, P = 0.0002), and also demonstrated superior ORR (32.5 % vs. 9.3 %, P = 0.0089) and DCR (87.5 % vs. 53.5 %, P = 0.0007). Median OS was observed at 12.0 months in the combination group vs. 10.9 months in the monotherapy group (HR = 0.82, 95 % CI: 0.47-1.43, P = 0.4803). For patients previously treated with immunotherapy, the median PFS was notably longer at 7.8 vs. 1.7 months (HR = 0.22, 95 % CI: 0.09-0.51, P = 0.0290). The incidence of grade ≥ 3 treatment-related adverse events, predominantly leukopenia (15.0 % vs. 7.0 %) and neutropenia (10.0 % vs. 5.0 %), was manageable across both groups.
CONCLUSION
Anlotinib plus docetaxel offers a viable therapeutic alternative for patients with advanced NSCLC who failed first-line platinum-based treatments.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Docetaxel; Male; Lung Neoplasms; Female; Middle Aged; Aged; Indoles; Antineoplastic Combined Chemotherapy Protocols; Quinolines; Adult; Neoplasm Staging; Treatment Outcome; Aged, 80 and over
PubMed: 38552544
DOI: 10.1016/j.lungcan.2024.107538 -
Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer.Cell Reports. Medicine Feb 2024Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of...
Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of docetaxel resistance constitutes a major clinical challenge. Here, we demonstrate activation of the cholinergic muscarinic M1 receptor (CHRM1) in CRPC cells upon acquiring resistance to docetaxel, which is manifested in tumor tissues from PC patients post- vs. pre-docetaxel. Genetic and pharmacological inactivation of CHRM1 restores the efficacy of docetaxel in resistant cells. Mechanistically, CHRM1, via its first and third extracellular loops, interacts with the SEMA domain of cMET and forms a heteroreceptor complex with cMET, stimulating a downstream mitogen-activated protein polykinase program to confer docetaxel resistance. Dicyclomine, a clinically available CHRM1-selective antagonist, reverts resistance and restricts the growth of multiple docetaxel-resistant CRPC cell lines and patient-derived xenografts. Our study reveals a CHRM1-dictated mechanism for docetaxel resistance and identifies a CHRM1-targeted combinatorial strategy for overcoming docetaxel resistance in PC.
Topics: Male; Humans; Docetaxel; Receptor, Muscarinic M1; Prostatic Neoplasms, Castration-Resistant; Cell Line, Tumor; Cholinergic Agents
PubMed: 38262412
DOI: 10.1016/j.xcrm.2023.101388 -
Heliyon Nov 2023RNA modification, including m6A, m5C, m1A, and m7G, participated in tumor progress. Therefore, the purpose of the present study was to explore the role of...
BACKGROUND
RNA modification, including m6A, m5C, m1A, and m7G, participated in tumor progress. Therefore, the purpose of the present study was to explore the role of m6A/m5C/m1A/m7G regulatory genes in the prognosis and tumor microenvironment (TME) for hepatocellular carcinoma (HCC).
METHODS
71 m6A/m5C/m1A/m7G regulatory genes expression for HCC was detected, differentially expressed genes were screened, and molecular forms were classified by unsupervised consensus clustering. Cox regression and the Least Absolute Shrinkage and Selection Operator (LASSO) analysis were applied to establish a prognostic signature. Time-dependent receiver operating characteristic (ROC) curves were evaluated for clinical effectiveness and accuracy of the prognostic hazard model. In cluster subtypes and risk models, the differences in prognosis, immune cell infiltration, immune checkpoint, immunotherapy, and drug sensitivity between different subtypes were evaluated.
RESULTS
HCC patients were classified into two clusters (cluster 1 and cluster 2) according to the expression of 71 m6A/m5C/m1A/m7G regulatory genes. Cluster 1 had a poor prognosis and different immune cell infiltration. Cluster 1 had higher immune checkpoint expression and TIDE score than cluster 2. Subsequently, we construct a five-gene prognostic model of m6A/m5C/m1A/m7G regulatory genes (YTHDF2, YTHDF1,YBX1, TRMT61A, TRMT10C). The Kaplan-Meier and ROC curve analysis showed that the prognostic signature exhibited good predictability. The risk score was considered an independent poor prognostic index. The high-risk group had higher immune checkpoint expression and higher TIDE scores. 5-Fluorouracil, docetaxel, doxorubicin, etoposide, gemcitabine, paclitaxel, sorafenib, and vinblastine were more suitable for high-risk patients. ECM receptor interaction, cell cycle, and Leishmania infection were enriched in the high-risk group.
CONCLUSION
The clustering subgroups and prognostic model of m6A/m5C/m1A/m7G regulatory genes were linked with bad prognosis and TME for HCC, and had the potential to be a novel tool to evaluate the outcomes of HCC patients.
PubMed: 38027812
DOI: 10.1016/j.heliyon.2023.e21285 -
Frontiers in Endocrinology 2023Male testicular dysfunction is a considerable complication of anti-cancer therapies, including chemotherapy and radiotherapy, partly due to the increased oxidative... (Meta-Analysis)
Meta-Analysis
Protective effects of exogenous melatonin therapy against oxidative stress to male reproductive tissue caused by anti-cancer chemical and radiation therapy: a systematic review and meta-analysis of animal studies.
BACKGROUND
Male testicular dysfunction is a considerable complication of anti-cancer therapies, including chemotherapy and radiotherapy, partly due to the increased oxidative stress caused by these treatments. Melatonin is an effective antioxidant agent that protects testicles against physical and toxic chemical stressors in animal models. This study aims to systematically review the melatonin's protective effects against anti-cancer stressors on rodential testicular tissue.
MATERIALS AND METHOD
An extensive search was conducted in Web of Science, Scopus, and PubMed for animal studies investigating exogenous melatonin's protective effects on rodent testicles exposed to anti-cancer chemicals and radiotherapeutic agents. Using the DerSimonian and Laird random-effect model, standardized mean differences and 95% confidence intervals were estimated from the pooled data. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022355293).
RESULTS
The meta-analysis included 38 studies from 43 studies that were eligible for the review. Rats and mice were exposed to radiotherapy (ionizing radiations such as gamma- and roentgen radiation and radioactive iodine) or chemotherapy (methotrexate, paclitaxel, busulfan, cisplatin, doxorubicin, vinblastine, bleomycin, cyclophosphamide, etoposide, Taxol, procarbazine, docetaxel, and chlorambucil). According to our meta-analysis, all outcomes were significantly improved by melatonin therapy, including sperm quantity and quality (count, motility, viability, normal morphology, number of spermatogonia, Johnsen's testicular biopsy score, seminiferous tubular diameter, and seminiferous epithelial height), serum level of reproductive hormones (Follicle-Stimulating Hormone and testosterone), tissue markers of oxidative stress (testicular tissue malondialdehyde, superoxide dismutase, glutathione peroxidase, catalase, glutathione, caspase-3, and total antioxidant capacity), and weight-related characteristics (absolute body, epididymis, testis, and relative testis to body weights). Most SYRCLE domains exhibited a high risk of bias in the included studies. Also, significant heterogeneity and small-study effects were detected.
CONCLUSION
In male rodents, melatonin therapy was related to improved testicular histopathology, reproductive hormones, testis and body weights, and reduced levels of oxidative markers in testicular tissues of male rodents. Future meticulous studies are recommended to provide a robust scientific backbone for human applications.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022355293, identifier CRD42022355293.
Topics: Humans; Male; Animals; Rats; Mice; Melatonin; Antioxidants; Iodine Radioisotopes; Semen; Thyroid Neoplasms; Oxidative Stress; Body Weight
PubMed: 37701901
DOI: 10.3389/fendo.2023.1184745