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Journal of the American Veterinary... Jul 2024To report the clinical characteristics, treatments, and outcomes in a cohort of dogs with histologically confirmed retroperitoneal sarcoma (RPS) and to identify...
OBJECTIVE
To report the clinical characteristics, treatments, and outcomes in a cohort of dogs with histologically confirmed retroperitoneal sarcoma (RPS) and to identify potential variables of prognostic significance.
ANIMALS
46 client-owned dogs from 10 clinics with histopathologic diagnosis of a sarcoma originating from the retroperitoneal space.
METHODS
Medical records were retrospectively reviewed to obtain information regarding clinical characteristics, treatments, and outcomes. Recorded variables were analyzed to report descriptive data for all cases and overall survival time. Multivariate analysis was utilized to evaluate prognostic factors for overall survival.
RESULTS
Hemangiosarcoma was the most common histologic subtype diagnosed (76.1%). Cytoreductive and curative intent surgical excision of the RPS was attempted in 12 and 22 dogs, respectively; 12 dogs underwent no surgery or had an exploratory laparotomy with incisional biopsy only. Nineteen dogs received adjuvant chemotherapy, either injectable or metronomic, and 1 dog received adjuvant radiation therapy. Fourteen of the 34 (41.2%) surgically treated dogs developed evidence of local recurrence, but there was no difference in local recurrence when comparing dogs categorized as curative intent versus cytoreductive surgery. The median overall survival time was 238 days. On multivariable analysis, treatment approach was associated with survival with surgical excision (vs palliative treatment) and adjuvant chemotherapy following surgery being protective against death. A diagnosis of hemangiosarcoma was associated with a greater hazard of death.
CLINICAL RELEVANCE
This study demonstrates a substantially greater survival time than previously published and suggests a survival benefit from surgical excision and adjuvant chemotherapy.
Topics: Animals; Dogs; Dog Diseases; Sarcoma; Retroperitoneal Neoplasms; Male; Female; Retrospective Studies; Treatment Outcome; Survival Analysis; Cohort Studies; Hemangiosarcoma
PubMed: 38382204
DOI: 10.2460/javma.23.09.0507 -
Breast (Edinburgh, Scotland) Apr 2024Single-agent oral vinorelbine is a standard of care for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer... (Randomized Controlled Trial)
Randomized Controlled Trial
Single-agent metronomic versus weekly oral vinorelbine as first-line chemotherapy in patients with HR-positive/HER2-negative advanced breast cancer: The randomized Tempo Breast study.
INTRODUCTION
Single-agent oral vinorelbine is a standard of care for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) that has progressed on endocrine therapy. Metronomic administration may offer a better balance of efficacy and safety than standard regimens, but data from previous trials are scarce.
METHODS
In this open-label, multicenter, phase II trial, patients were randomized to oral vinorelbine administered on a metronomic (50 mg three times weekly) or weekly (60 mg/m in cycle 1, increasing to 80 mg/m if well tolerated) schedule. Treatment was continued until disease progression or intolerance. The primary endpoint was disease control rate (DCR, the proportion of patients with a best overall confirmed response of CR, PR, or stable disease lasting 6 months or more).
RESULTS
One-hundred sixty-three patients were randomized and treated. The DCR was 63.4% (95% confidence interval [CI]: 52.0-73.8) with metronomic vinorelbine and 72.8% (95% CI: 61.8-82.1) with weekly vinorelbine. Weekly vinorelbine was also associated with longer progression-free survival (5.6 vs 4.0 months) and overall survival (26.7 vs 22.3 months) than metronomic vinorelbine, but was associated with more adverse events.
CONCLUSIONS
In this randomized phase II trial, single-agent metronomic oral vinorelbine was effective and well tolerated as first-line chemotherapy for patients with HR-positive/HER2-negative ABC. Formal comparisons are not done in this phase II study and one can simply observe that confidence intervals of all endpoints overlap. When deciding for a chemotherapy after failure of endocrine therapy and CDK 4/6 inhibitors, oral vinorelbine might be an option to be given with either schedule.
CLINICAL TRIAL REGISTRATION NUMBER
EudraCT 2014-003860-19.
Topics: Humans; Female; Vinorelbine; Breast Neoplasms; Breast; Receptor, ErbB-2; Progression-Free Survival; Administration, Metronomic; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Vinblastine
PubMed: 38377732
DOI: 10.1016/j.breast.2024.103681 -
Cancer Research and Treatment Feb 2024To investigate the efficacy and safety of using metronomic S1 adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma (LANPC).
PURPOSE
To investigate the efficacy and safety of using metronomic S1 adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma (LANPC).
MATERIALS AND METHODS
We retrospectively collected data on patients diagnosed with LANPC between January 2016 and December 2021. All patients were treated with induction chemotherapy and concurrent chemoradiotherapy with or without metronomic chemotherapy (MC). Toxicities during MC were recorded. The chi-square test, Kaplan-Meier methods, propensity score matching (PSM), and Cox proportional hazards model were used for statistical analyses.
RESULTS
A total of 474 patients were identified, including 64 (13.5%) and 410 (83.5%) patients with or without receiving MC, respectively. Patients who received metronomic S1 had significantly better 3-year locoregional recurrence-free survival (LRFS) (100% vs. 90.9%, p=0.038), distant metastasis-free survival (DMFS) (98.5% vs. 84.1%, p=0.002), disease-free survival (DFS) (98.4% vs. 77.5%, p<0.001), and overall survival (OS) (98.0% vs. 87.7%, p=0.008) compared to those without metronomic S1. The multivariate prognostic analysis revealed that metronomic S1 was identified as an independent prognostic factor associated with better DMFS (hazard ratio [HR] 0.074, p=0.010), DFS (HR 0.103, p=0.002) and OS (HR 0.127, P=0.042), but not in LRFS (p=0.071). Similar results were found using PSM. Common adverse events observed in the metronomic S1 group included leukopenia, neutropenia, increased total bilirubin, anorexia, rash/desquamation, and hyperpigmentation. All patients with adverse events were grade 1-2.
CONCLUSION
It is worth conducting a randomized controlled trial to assess the effect of metronomic S1 on survival outcomes and toxicities of LANPC.
PubMed: 38374697
DOI: 10.4143/crt.2023.1343 -
Molecular Cancer Feb 2024Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients...
Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin's antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781.
Topics: Humans; Trabectedin; Prospective Studies; Antineoplastic Agents, Alkylating; Sarcoma; Cyclophosphamide; Dioxoles; Tumor Microenvironment
PubMed: 38374062
DOI: 10.1186/s12943-024-01942-y -
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 -
Journal of Cancer Research and Clinical... Feb 2024In some patients with prostate cancer, bone marrow carcinomatosis develops later in the course of the disease, which has a poor prognosis. These are often heavily...
PURPOSE
In some patients with prostate cancer, bone marrow carcinomatosis develops later in the course of the disease, which has a poor prognosis. These are often heavily pretreated patients in the castration-resistant situation for whom there are no other therapeutic options, because either all available systemic therapies have already been used or the use of one is not possible due to the cytopenias associated with bone marrow carcinomatosis. In our literature search, there are no data on this treatment in the setting available, especially no clinical trial or even randomized data. This case series is to determine the clinical efficacy of metronomic cyclophosphamide in patients with metastatic castration-resistant prostate cancer and bone marrow carcinomatosis, particularly with regard to stabilization of the blood count (thrombocytopenias) and thus the possibility of further (more toxic) lines of therapy.
METHODS
Retrospective unicenter analysis was performed on eleven patients between 54 and 84 years of age on metronomic cyclophosphamide for bone marrow carcinomatosis in metastatic castration-resistant prostate cancer treated at a Swiss cancer center between 2014 and 2023.
RESULTS
Eleven patients received metronomic cyclophosphamide for varying periods of time; the majority had severe cytopenias (especially thrombocytopenias). Partially hematologic stabilization was achieved with administration of further systemic therapies.
CONCLUSION
Our case series demonstrates that the use of metronomic cyclophosphamide allows hematologic stabilization for months, benefiting patients who had already received all available therapies for metastatic castration-resistant prostate cancer. Alternatively, it may act as bridging therapy to allow consecutive administration of more toxic therapies with proven survival benefit.
Topics: Humans; Male; Bone Marrow; Cyclophosphamide; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Thrombocytopenia; Middle Aged; Aged; Aged, 80 and over; Bone Marrow Neoplasms
PubMed: 38329600
DOI: 10.1007/s00432-023-05525-0 -
Heliyon Feb 2024Cancer represents a significant global health and economic burden due to its high mortality rates. While effective in some instances, traditional chemotherapy often... (Review)
Review
Cancer represents a significant global health and economic burden due to its high mortality rates. While effective in some instances, traditional chemotherapy often falls short of entirely eradicating various types of cancer. It can cause severe side effects due to harm to healthy cells. Two therapeutic approaches have risen to the forefront to address these limitations: metronomic chemotherapy (MCT) and drug repurposing. Metronomic chemotherapy is an innovative approach that breaks from traditional models. It involves the administration of chemotherapeutic regimens at lower doses, without long drug-free intervals that have previously been a hallmark of such treatments. This method offers a significant reduction in side effects and improved disease management. Simultaneously, drug repurposing has gained considerable attraction in cancer treatment. This approach involves utilizing existing drugs, initially developed for other therapeutic purposes, as potential cancer treatments. The application of known drugs in a new context accelerates the timeline from laboratory to patient due to pre-existing safety and dosage data. The intersection of these two strategies gives rise to a novel therapeutic approach named 'Metronomics.' This approach encapsulates the benefits of both MCT and drug repurposing, leading to reduced toxicity, potential for oral administration, improved patient quality of life, accelerated clinical implementation, and enhanced affordability. Numerous clinical studies have endorsed the efficacy of metronomic chemotherapy with tolerable side effects, underlining the potential of Metronomics in better cancer management, particularly in low- and middle-income countries. This review underscores the benefits and applications of metronomic chemotherapy and drug repurposing, specifically in the context of breast cancer, showcasing the promising results of pre-clinical and clinical studies. However, we acknowledge the necessity of additional clinical investigations to definitively establish the role of metronomic chemotherapy in conjunction with other treatments in comprehensive cancer management.
PubMed: 38314272
DOI: 10.1016/j.heliyon.2024.e24670 -
Cancer Letters Apr 2024Metronomic chemotherapy refers to the consistent and regular administration of low-dose chemotherapeutic agents over an extended period, with minimal or no extended... (Review)
Review
Metronomic chemotherapy refers to the consistent and regular administration of low-dose chemotherapeutic agents over an extended period, with minimal or no extended drug-free intervals. The effectiveness of metronomic chemotherapy is derived from its capacity to impede tumor angiogenesis and foster antitumor immune responses, rather than merely interrupting tumor cell mitosis. Metronomic chemotherapy has been applied in the treatment of neuroblastoma for decades, including patients with newly diagnosed high-risk neuroblastoma and relapsed or refractory neuroblastoma. In the modern era of neuroblastoma treatment, metronomic chemotherapy remains a viable option for maintenance therapy in newly diagnosed neuroblastoma patients without access to autologous stem cell transplantation or immunotherapy, especially in resource-limited regions. For relapsed or refractory patients, metronomic chemotherapy is a suitable alternative for individuals intolerant to intensified treatments or receiving palliative care. Cyclophosphamide, etoposide, vinca alkaloids, and celecoxib constitute the primary components of current metronomic chemotherapy. Given the need for additional research to determine the optimal regimen, comprehensive studies must be conducted to explore and establish standardized metronomic chemotherapy protocols. Additionally, investigating potential biomarkers and clinical prognostic factors is imperative for future advancements in this field.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Antineoplastic Combined Chemotherapy Protocols; Transplantation, Autologous; Neuroblastoma; Cyclophosphamide; Administration, Metronomic
PubMed: 38311055
DOI: 10.1016/j.canlet.2024.216617 -
European Journal of Cancer (Oxford,... Mar 2024Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype, with dismal prognosis and limited option in advanced settings, yet stromal tumor...
Multiplexed high-throughput immune cell imaging in patients with high-risk triple negative early breast cancer: Analysis from the International Breast Cancer Study Group (IBCSG) Trial 22-00.
BACKGROUND
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype, with dismal prognosis and limited option in advanced settings, yet stromal tumor infiltrating lymphocytes (sTILs) in this subtype has a predictive role.
PATIENTS AND METHODS
The International Breast Cancer Study Group (IBCSG) Trial 22-00 is a randomized phase III clinical trial testing the efficacy of low-dose metronomic oral Cyclophosphamide-Methotrexate (CM) maintenance following standard adjuvant chemotherapy treatment for early-stage hormone receptor-negative breast cancer patients. A case-cohort sampling was used. We characterized immune cells infiltrates in patients with TNBC by 6 plex immunofluorescence (IF) staining for CD4, FOXP3, CD3, cytokeratine and CD8 RESULTS: We confirmed that high immune CD3 T cells as well as stromal and intra-epithelial Tregs (CD4Foxp3 T cells) infiltrates were associated with a better Distant Recurrence-Free Interval (DRFI), especially in LN+ patient, regardless of the treatment. More importantly, we showed that the spatial distribution of immune cells at baseline is crucial, as CM maintenance was detrimental for T cells excluded LN+ TNBC patients.
CONCLUSIONS
immune spatial classification on immune cells infiltrates seems crucial and could help patients' selection in clinical trial and greatly improve responses to specific therapies.
Topics: Humans; Biomarkers, Tumor; Cyclophosphamide; Disease-Free Survival; Forkhead Transcription Factors; Lymphocytes, Tumor-Infiltrating; Methotrexate; Prognosis; Triple Negative Breast Neoplasms; Female; Randomized Controlled Trials as Topic; Clinical Trials, Phase III as Topic
PubMed: 38309015
DOI: 10.1016/j.ejca.2024.113535 -
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