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JAMA Network Open May 2024The treatment paradigm for advanced urothelial carcinoma (aUC) has undergone substantial transformation due to the introduction of effective, novel therapeutic agents....
IMPORTANCE
The treatment paradigm for advanced urothelial carcinoma (aUC) has undergone substantial transformation due to the introduction of effective, novel therapeutic agents. However, outcomes remain poor, and little is known about current treatment approaches and attrition rates for patients with aUC.
OBJECTIVES
To delineate evolving treatment patterns and attrition rates in patients with aUC using a US-based patient-level sample.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study used patient-level data from the nationwide deidentified electronic health record database Flatiron Health, originating from approximately 280 oncology clinics across the US. Patients included in the analysis received treatment for metastatic or local aUC at a participating site from January 1, 2011, to January 31, 2023. Patients receiving treatment for 2 or more different types of cancer or participating in clinical trials were excluded from the analysis.
MAIN OUTCOMES AND MEASURES
Frequencies and percentages were used to summarize the (1) treatment received in each line (cisplatin-based regimens, carboplatin-based regimens, programmed cell death 1 and/or programmed cell death ligand 1 [PD-1/PD-L1] inhibitors, single-agent nonplatinum chemotherapy, enfortumab vedotin, erdafitinib, sacituzumab govitecan, or others) and (2) attrition of patients with each line of therapy, defined as the percentage of patients not progressing to the next line.
RESULTS
Of the 12 157 patients within the dataset, 7260 met the eligibility criteria and were included in the analysis (5364 [73.9%] men; median age at the start of first-line treatment, 73 [IQR, 66-80] years). All patients commenced first-line treatment; of these, only 2714 (37.4%) progressed to receive second-line treatment, and 857 (11.8%) advanced to third-line treatment. The primary regimens used as first-line treatment contained carboplatin (2241 [30.9%]), followed by PD-1/PD-L1 inhibitors (2174 [29.9%]). The PD-1/PD-L1 inhibitors emerged as the predominant choice in the second- and third-line (1412 of 2714 [52.0%] and 258 of 857 [30.1%], respectively) treatments. From 2019 onward, novel therapeutic agents were increasingly used in second- and third-line treatments, including enfortumab vedotin (219 of 2714 [8.1%] and 159 of 857 [18.6%], respectively), erdafitinib (39 of 2714 [1.4%] and 28 of 857 [3.3%], respectively), and sacituzumab govitecan (14 of 2714 [0.5%] and 34 of 857 [4.0%], respectively).
CONCLUSIONS AND RELEVANCE
The findings of this cohort study suggest that approximately two-thirds of patients with aUC did not receive second-line treatment. Most first-line treatments do not include cisplatin-based regimens and instead incorporate carboplatin- or PD-1/PD-L1 inhibitor-based therapies. These data warrant the provision of more effective and tolerable first-line treatments for patients with aUC.
Topics: Humans; Male; Female; Retrospective Studies; Aged; United States; Carboplatin; Middle Aged; Carcinoma, Transitional Cell; Immune Checkpoint Inhibitors; Urologic Neoplasms; Urinary Bladder Neoplasms; Cisplatin; Antineoplastic Combined Chemotherapy Protocols; Aged, 80 and over; Antineoplastic Agents; Antibodies, Monoclonal
PubMed: 38696168
DOI: 10.1001/jamanetworkopen.2024.9417 -
BMC Cancer Aug 2023Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various...
Comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for low-risk gestational trophoblastic neoplasia (FIGO Score 0-4): study protocol for a prospective, multicentre, randomized trial.
BACKGROUND
Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various methotrexate-based and actinomycin D-based single-agent regimens can be used. However, there is insufficient evidence to determine the superior regimen. To guide doctors in selecting a single-agent chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia, we will compare two regimens.
METHODS
We will conduct a multicentre, randomized, prospective clinical trial. Selected low-risk gestational trophoblastic neoplasia patients (FIGO score 0-4) will be randomized 1:1 to a biweekly single-dose actinomycin D group or a multiday methotrexate therapy group. The actinomycin D group will receive IV pulse actinomycin D (1.25 mg/m) every 14 days, and the methotrexate group will receive methotrexate (50 mg) intramuscularly on days 1, 3, 5, and 7 (4 doses per cycle) and leucovorin (15 mg) intramuscularly on days 2, 4, 6, and 8. This process will be repeated every 14 days. The primary endpoints will include the complete remission rate by single-agent therapy and the overall complete remission rate. The secondary endpoints will include the duration needed to achieve complete remission after single-agent chemotherapy, number of courses needed to achieve complete remission after single-agent chemotherapy, incidence and severity of adverse effects, effects on menstrual conditions and ovarian function based on the anti-Mullerian hormone level, and patient-reported quality of life.
DISCUSSION
Previous clinical trials comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for treating low-risk gestational trophoblastic neoplasia patients failed to meet the expected case number. Through this multicentre study, the complete remission ratio and efficacy difference between biweekly single-dose actinomycin D and multiday methotrexate therapy will be obtained. This study will also provide the basis for formulating a preferred regimen for treating patients with low-risk gestational trophoblastic neoplasia.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT04562558, Registered on 13 September 2020 (Protocol version 2020-9-24, version 1.0).
Topics: Humans; Pregnancy; Female; Dactinomycin; Methotrexate; Prospective Studies; Quality of Life; Gestational Trophoblastic Disease; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37612621
DOI: 10.1186/s12885-023-11225-2 -
Frontiers in Oncology 2023Cell cycle arrest (CCA) is seen as a prime candidate for effective cancer therapy. This mechanism can help researchers to create new treatments to target cancer cells at... (Review)
Review
Cell cycle arrest (CCA) is seen as a prime candidate for effective cancer therapy. This mechanism can help researchers to create new treatments to target cancer cells at particular stages of the cell cycle (CC). The CCA is a characteristic of various therapeutic modalities, including radiation (RT) and chemotherapy (CT), which synchronizes the cells and facilitates the standardization of radio-chemotherapy protocols. Although it was discovered that photodynamic treatment (PDT) had a biological effect on CCA in cancer cells, the mechanism remains unclear. Furthermore, besides conventional forms of cell death such as apoptosis, autophagy, and necrosis, various unconventional types of cell death including pyroptosis, mitotic catastrophe, paraptosis, ferroptosis, necroptosis, and parthanatos after PDT have been reported. Thus, a variety of elements, such as oxygen, the tumor's microenvironment, the characteristics of light, and photosensitizer (PS), influence the effectiveness of the PDT treatment, which have not yet been studied clearly. This review focuses on CCA induced by PDT for a variety of PSs agents on various cell lines. The CCA by PDT can be viewed as a remarkable effect and instructive for the management of the PDT protocol. Regarding the relationship between the quantity of reactive oxygen species (ROS) and its biological consequences, we have proposed two mathematical models in PDT. Finally, we have gathered recent and studies about CCA post-PDT at various stages and made suggestions about how it can standardize, potentiate, and customize the PDT methodology.
PubMed: 37503319
DOI: 10.3389/fonc.2023.1225694 -
Military Medicine Nov 2023Noncompressible torso hemorrhage is the leading cause of exsanguination on the battlefield. A self-expanding, intraperitoneal deployed, thermoreversible foam has been...
INTRODUCTION
Noncompressible torso hemorrhage is the leading cause of exsanguination on the battlefield. A self-expanding, intraperitoneal deployed, thermoreversible foam has been developed that can be easily administered by a medic in austere settings to temporarily tamponade noncompressible torso hemorrhage. The purpose of this study was to assess the long-term safety and physical characteristics of using Fast Onset Abdominal Management (FOAM; Critical Innovations LLC) in swine.
MATERIALS AND METHODS
Yorkshire swine (40-60 kg) were sedated, intubated, and placed on ventilatory support. An external jugular catheter was placed for sampling of blood. Continuous heart rate, temperature, saturation of peripheral oxygen, end-tidal carbon dioxide, and peak airway pressures were monitored for a 4-hour period after intervention (i.e., FOAM agent injection or a sham introducer without agent delivery). The FOAM agent was injected to obtain an intra-abdominal pressure of 60 mmHg for at least 10 minutes. After 4 hours, the animals were removed from ventilatory support and returned to their housing for a period of 7-14 days. Group size analysis was not performed, as this was a descriptive safety study. Blood samples were obtained at baseline and at 1-hour post-intervention and then on days 1, 3, 7, and 14. Euthanasia, necropsy, and harvesting of samples for histologic analysis (from kidneys, terminal ilium, liver, pancreas, stomach, spleen, and lungs) were performed upon expiration. Histologic scoring for evidence of ischemia, necrosis, and abdominal compartment sequela was blinded and reported by semi-quantitative scale (range 0-4; 0 = no change, 1 = minimal, 2 = mild, 3 = moderate, and 4 = marked). Oregon Health & Science University's Institutional Animal Care and Use Committee, as well as the U.S. Army Animal Care and Use Review Office, approved this protocol before the initiation of experiments (respectively, protocol numbers IP00003591 and MT180006.e002).
RESULTS
Five animals met a priori inclusion criteria, and all of these survived to their scheduled endpoints. Two animals received sham injections of the FOAM agent (one euthanized on day 7 and one on day 14), and three animals received FOAM agent injections (one euthanized on day 7 and two on day 14). A transitory increase in creatinine and lactate was detected during the first day in the FOAM injected swine but resolved by day 3. No FOAM agent was observed in the peritoneal cavity upon necropsy at day 7 or 14. Histologic data revealed no clinically relevant differences in any organ system between intervention and control animals upon sacrifice at day 7 or 14.
CONCLUSIONS
This study describes the characteristics, survival, and histological analysis of using FOAM in a porcine model. In our study, FOAM reached the desired intra-abdominal pressure endpoint while not significantly altering basic hematologic parameters, except for transient elevations of creatinine and lactate on day 1. Furthermore, there was no clinical or histological relevant evidence of ischemia, necrosis, or intra-abdominal compartment syndrome. These results provide strong support for the safety of the FOAM device and will support the design of further regulatory studies in swine and humans.
Topics: Humans; Swine; Animals; Creatinine; Abdominal Injuries; Hemorrhage; Torso; Necrosis; Lactates; Ischemia
PubMed: 35820028
DOI: 10.1093/milmed/usac206 -
Biomedicine & Pharmacotherapy =... Sep 2023Ovarian cancer is a highly lethal disease that affects women. Early diagnosis and treatment of women with early-stage disease improve the probability of survival.... (Review)
Review
Ovarian cancer is a highly lethal disease that affects women. Early diagnosis and treatment of women with early-stage disease improve the probability of survival. Unfortunately, the majority of women with ovarian cancer are diagnosed at advanced stages 3 and 4 which makes treatment challenging. While the majority of the patients respond to first-line treatment, i.e. cytoreductive surgery integrated with platinum-based chemotherapy, the rate of disease recurrence is very high and the available treatment options for recurrent disease are not curative. Thus, there is a need for more effective treatment options for ovarian cancer. Targeted drug conjugate systems have emerged as a promising therapeutic strategy for the treatment of ovarian cancer. These systems provide the opportunity to selectively deliver highly potent chemotherapeutic drugs to ovarian cancer, sparing healthy normal cells. Thus, the effectiveness of the drugs is improved and systemic toxicity is greatly reduced. In this review, different targeted drug conjugate systems that have been or are being developed for the treatment of ovarian cancer will be discussed.
Topics: Humans; Female; Neoplasm Recurrence, Local; Ovarian Neoplasms; Treatment Outcome; Chemotherapy, Adjuvant; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents
PubMed: 37473683
DOI: 10.1016/j.biopha.2023.115151 -
Cancer Letters Jul 2024In patients with ER + metastatic breast cancer (mBC), the first-line treatment involves the combination of endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i)....
In patients with ER + metastatic breast cancer (mBC), the first-line treatment involves the combination of endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). However, a significant group of patients experiences disease progression, emphasizing the urgent clinical need to identify novel anti-tumor therapies. We previously generated breast cancer cells resistant to the combination of fulvestrant (ER downregulator) and abemaciclib (CDK4/6 inhibitor) from MCF7 and T47D (MCF7-FAR and T47D-FAR). RNA-seq-based Gene Set Enrichment Analysis (GSEA) revealed hyper-activation of EGFR, HER2, and AKT signaling in both MCF7-FAR and T47D-FAR. Modulating EGFR or ERBB2 expression through loss- and gain-of-function experiments altered tumor sensitivity to fulvestrant and abemaciclib in parental and FAR spheroids, affecting ERK and AKT/S6 pathways. Cetuximab treatment overcame tumor resistance to fulvestrant and abemaciclib in FAR and EGFR-overexpressing breast cancer spheroids and xenografts. Likewise, patient-derived organoids (PDOs) from individuals with ER + mBC, progressing on palbociclib, exhibited up-regulation of EGFR and HER2 pathways. In conclusion, our findings suggest that inhibiting EGFR and HER2 pathways might overcome resistance to ET + CDK4/6i in selected patients with ER + mBC.
Topics: Humans; Breast Neoplasms; Receptor, ErbB-2; Female; Drug Resistance, Neoplasm; Cyclin-Dependent Kinase 4; Animals; ErbB Receptors; Cyclin-Dependent Kinase 6; Receptors, Estrogen; Mice; Fulvestrant; Protein Kinase Inhibitors; Benzimidazoles; Aminopyridines; Xenograft Model Antitumor Assays; Antineoplastic Agents, Hormonal; MCF-7 Cells; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38788968
DOI: 10.1016/j.canlet.2024.216968 -
Cells Aug 2023Different conventional therapeutic procedures are utilized globally to manage cancer cases, yet the mortality rate in patients with cancer remains considerably high.... (Review)
Review
Different conventional therapeutic procedures are utilized globally to manage cancer cases, yet the mortality rate in patients with cancer remains considerably high. Developments in the field of nanotechnology have included novel therapeutic strategies to deal with cancer. Biogenic (green) metallic silver nanoparticles (AgNPs) obtained using plant-mediated protocols are attractive to researchers exploring cancer treatment. Biogenic AgNPs present advantages, since they are cost-effective, easy to obtain, energy efficient, and less toxic compared to chemically and physically obtained AgNPs. Also, they present excellent anticancer abilities thanks to their unique sizes, shapes, and optical properties. This review provides recent advancements in exploring biogenic AgNPs as a drug or agent for cancer treatment. Thus, great attention was paid to the anticancer efficacy of biogenic AgNPs, their anticancer mechanisms, their efficacy in cancer photodynamic therapy (PDT), their efficacy in targeted cancer therapy, and their toxicity.
Topics: Silver; Neoplasms; Metal Nanoparticles; Humans; Animals; Antineoplastic Agents; Photochemotherapy; Nanoparticle Drug Delivery System
PubMed: 37566091
DOI: 10.3390/cells12152012 -
BMJ Open Nov 2023Head and neck cancer is the eighth most common cancer in the UK. Current standard of care treatment for patients with recurrent/metastatic squamous cell head and neck...
Protocol for the EACH trial: a multicentre phase II study evaluating the safety and antitumour activity of the combination of avelumab, an anti-PD-L1 agent, and cetuximab, as any line treatment for patients with recurrent/metastatic head and neck squamous cell cancer (HNSCC) in the UK.
INTRODUCTION
Head and neck cancer is the eighth most common cancer in the UK. Current standard of care treatment for patients with recurrent/metastatic squamous cell head and neck carcinoma (HNSCC) is platinum-based chemotherapy combined with the anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, cetuximab. However, most patients will have poor median overall survival (OS) of 6-9 months despite treatment. HNSCC tumours exhibit an immune landscape poised to respond to immunotherapeutic approaches, with most tumours expressing the immunosuppressive receptor programmed death-ligand 1 (PD-L1). We undertook the current study to determine the safety and efficacy of avelumab, a monoclonal antibody targeting the interaction between PD-L1 and its receptor on cytotoxic T-cells, in combination with cetuximab.
METHODS AND ANALYSIS
This is a multi-centre, single-arm dose de-escalation phase II safety and efficacy study of avelumab combined with cetuximab; the study was to progress to a randomised phase II trial, however, the study will now complete after the safety run-in component. Up to 16 participants with histologically/cytologically recurrent/metastatic squamous cell carcinoma (including HNSCC) who have not received cetuximab previously will be recruited. All patients will receive 10 mg/kg avelumab and cetuximab (500, 400 or 300 mg/m depending on the cohort open at time of registration) on days 1 and 15 of 4-week cycles for up to 1 year, (avelumab not given cycle 1 day 1). A modified continual reassessment method will be used to determine dose de-escalation. The primary objective is to establish the safety of the combination and to determine the optimum dose of cetuximab. Secondary objectives include assessing evidence of antitumour activity by evaluating response rates and disease control rates at 6 and 12 months as well as progression-free and OS.
ETHICS AND DISSEMINATION
Approval granted by City and East REC (18/LO/0021). Findings will be published in peer-reviewed journals and disseminated at conferences.
TRIAL REGISTRATION NUMBER
NCT03494322.
Topics: Humans; Cetuximab; Squamous Cell Carcinoma of Head and Neck; B7-H1 Antigen; Neoplasm Recurrence, Local; Carcinoma, Squamous Cell; Antibodies, Monoclonal; Head and Neck Neoplasms; Antineoplastic Agents; United Kingdom; Antineoplastic Combined Chemotherapy Protocols; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Clinical Trials, Phase II as Topic
PubMed: 38011968
DOI: 10.1136/bmjopen-2022-070391 -
Taiwanese Journal of Obstetrics &... Nov 2023The current standard therapy of epithelial ovarian cancer (EOC) is the combination of surgery (primary cytoreductive surgery or interval cytoreductive surgery) and... (Review)
Review
The current standard therapy of epithelial ovarian cancer (EOC) is the combination of surgery (primary cytoreductive surgery or interval cytoreductive surgery) and platinum-based chemotherapy (mainly using paclitaxel and carboplatin either by neoadjuvant chemotherapy and/or by postoperative adjuvant chemotherapy) with/without adding targeted therapy (mainly using anti-angiogenesis agent- bevacizumab). After front-line chemotherapy, the advanced-stage EOC can be successfully controlled and three-quarters of patients can achieve a complete clinical remission. Unfortunately, nearly all patients will recur and progression-free survival (PFS) of these patients is seldom more than 3 years with a dismal median PFS of 12-18 months. With each recurrence, patients finally develop resistance to standard chemotherapy regimen, contributing to fewer than half of women who survive for more than 5 years after diagnosis with a median overall survival (OS) of 40.7 months. Due to the lower PFS and OS, particularly for those advanced-stage patients, novel therapeutic options during the front-line therapy are desperately needed to decrease the occurrence of recurrence, and the majority of them are still under investigation. It is well-known that overexpression of CA125 has been associated with attenuated cellular apoptosis, platinum chemotherapy resistance, tumor proliferation and disease progression, suggesting that anti-CA125 may play a role in the management of patients with EOC. The current review is a Part I which will focus on development of anti-CA125 monoclonal antibody, hoping that alternation of the front-line therapy by chemo-immunotherapy will be beneficial for prolonged survival of patients with EOC.
Topics: Humans; Female; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Paclitaxel; Carboplatin; Immunotherapy
PubMed: 38008497
DOI: 10.1016/j.tjog.2023.09.017 -
PloS One 2023Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates <10%. Treatment failure is due in... (Clinical Trial)
Clinical Trial
Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates <10%. Treatment failure is due in part to the function of the BBB. Intratumoral microdialysis sampling is an effective tool to determine brain entry of varied agents and could help to provide a better understanding of the relationship of drug permeability to DMG treatment responsivity. This is a non-randomized, single-center, phase 1 clinical trial. Up to seven young adult (18-39 years) patients with recurrent high-grade or diffuse midline glioma will be enrolled with the goal of 5 patients completing the trial over an anticipated 24 months. All patients will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. Patients will undergo resection or biopsy, placement of a microdialysis catheter, and 48 hours of dialysate sampling coupled with timed plasma collections. If intratumoral tumor or brain dialysate sampling concentrations are >10nmol/L, or tumor tissue studies demonstrate CDK inhibition, then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy and discontinued with evidence of radiologic or clinical disease progression. The poor survival associated with diffuse midline gliomas underscore the need for improved means to evaluate efficacy of drug delivery to tumor and peritumoral tissue. The findings of this novel study, will provide real-time measurements of BBB function which have the potential to influence future prognostic and diagnostic decisions in such a lethal disease with limited treatment options. Trial registration: Clinicaltrials.gov, NCT05413304. Registered June 10, 2022, Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis.
Topics: Young Adult; Humans; Feasibility Studies; Microdialysis; Clinical Protocols; Dialysis Solutions; Glioma
PubMed: 37682953
DOI: 10.1371/journal.pone.0291068