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Cancer Letters Jun 2024Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting... (Review)
Review
Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting multiple targets and reducing toxicity of antineoplastic drugs. This minireview will summarize preclinical and clinical studies on cytotoxic drugs given at weekly, daily, or at continuous metronomic schedules alone or in combination with novel targeted agents for hematological malignancies, including lymphoma, multiple myeloma, and leukemia. Most of the preclinical in vitro and in vivo studies have reported a significant benefit of both mCHEMO monotherapy and combinatorial regimens compared with chemotherapy at the maximum tolerated dose. However, the combination of mCHEMO with targeted drugs is still little explored in the hematologic clinical setting. Data obtained from preclinical studies on low dose metronomic chemotherapy in hematological malignancies clearly suggested the possibility to clinically investigate more tolerable and effective strategies for the treatment of patients with advanced hematological malignancies, or at least for those frail and elderly patients, who are not eligible or resistant to standard treatments.
Topics: Humans; Administration, Metronomic; Hematologic Neoplasms; Antineoplastic Agents; Animals; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38636896
DOI: 10.1016/j.canlet.2024.216900 -
Breast Cancer (Dove Medical Press) 2024Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only... (Clinical Trial)
Clinical Trial
Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.
PURPOSE
Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not.
PATIENTS AND METHODS
We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes.
RESULTS
All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06).
CONCLUSION
This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.
PubMed: 38628818
DOI: 10.2147/BCTT.S447290 -
Breast (Edinburgh, Scotland) Jun 2024Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Phase II randomized trial comparing metronomic anthracycline-containing chemotherapy versus standard schedule in untreated HER2 negative advanced breast cancer: activity and quality of life results of the GOIM 21003 trial.
BACKGROUND
Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC.
METHODS
Patients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity.
RESULTS
From August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A).
CONCLUSIONS
First line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.
Topics: Humans; Female; Breast Neoplasms; Middle Aged; Quality of Life; Administration, Metronomic; Cyclophosphamide; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Receptor, ErbB-2; Progression-Free Survival; Drug Administration Schedule; Treatment Outcome; Anthracyclines; Polyethylene Glycols
PubMed: 38615483
DOI: 10.1016/j.breast.2024.103725 -
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 -
American Journal of Cancer Research 2024Distant metastasis is an important prognostic factor for oral squamous cell carcinoma (OSCC). It involves the direct spread of tumor cells through blood vessels or via...
Distant metastasis is an important prognostic factor for oral squamous cell carcinoma (OSCC). It involves the direct spread of tumor cells through blood vessels or via lymph nodes; however, there are currently no well-established treatments for its prevention in patients with OSCC. To investigate the impact of metronomic neoadjuvant chemotherapy on OSCC, we conducted a retrospective analysis of the efficacy of neoadjuvant chemotherapy with S-1 alone. Fifty-four patients underwent up-front surgery, while 106 received neoadjuvant chemotherapy with S-1 alone. A serious adverse event occurred in one of patient treated with neoadjuvant chemotherapy (1%); however, all patients underwent resection. The 5-year overall survival rate was higher with S-1 than with up-front surgery (96% vs. 81%, P = 0.002). Moreover, neoadjuvant chemotherapy significantly increased the overall survival rate of patients with poorly or moderately differentiated tumors, but not those with well-differentiated tumors. By analyzing a cohort of 523 head and neck squamous cell carcinoma (HNSCC) patients in the Cancer Genome Atlas, we identified genetic variants associated with histological differentiation. The frequency of pathogenic/likely pathogenic variants or deletions in 5 genes associated with HNSCC correlated with histological differentiation, some of which indicated the activation of the Wnt/β-catenin pathway in well-differentiated HNSCC. The vessel marker CD31 was highly expressed in poorly differentiated OSCC, whereas the anti-angiogenic molecule, LCN2, which is induced by the activation of the Wnt pathway, was highly expressed in well-differentiated OSCC. The present study showed that overall survival rates were higher in patients with poorly or moderately differentiated OSCC who received metronomic neoadjuvant chemotherapy, which was attributed to a difference in angiogenesis based on the characteristic landscape of pathogenic mutations according to histological differentiation.
PubMed: 38590400
DOI: 10.62347/EYNT8387 -
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 -
The Canadian Veterinary Journal = La... Apr 2024Effective treatment for canine oral malignant melanoma (, curative-intent surgery) may not be feasible or radiation therapy may be unavailable. However, chemotherapy is...
BACKGROUND
Effective treatment for canine oral malignant melanoma (, curative-intent surgery) may not be feasible or radiation therapy may be unavailable. However, chemotherapy is usually an option, and more information is needed regarding its use without adequate local treatments.
OBJECTIVE
Our objective was to investigate the efficacy of chemotherapy in canine oral malignant melanoma without adequate local control, using carboplatin with dose reduction in small-breed dogs and metronomic chemotherapy.
ANIMALS AND PROCEDURE
Client-owned dogs with histopathologically diagnosed oral malignant melanoma were retrospectively enrolled from 2016 to 2022. The chemotherapy protocol in each case was determined by the attending clinician.
RESULTS
Thirteen dogs were included. The median progression-free interval of all 13 dogs was 42 d (14 to 953 d). The median overall survival time of dogs with chemotherapy as their only systemic treatment was 181 d (50 to 960 d; = 11). The median dosage of carboplatin was 250 mg/m. Response to treatment and clinical stage were significant prognostic factors.
CONCLUSION AND CLINICAL RELEVANCE
As chemotherapy provided a median survival of 6 mo, it could be considered when adequate local control is infeasible. Earlier clinical stages or achievement of at least stable disease during chemotherapy may indicate better survival in dogs.
Topics: Humans; Dogs; Animals; Melanoma; Carboplatin; Retrospective Studies; Antineoplastic Agents; Mouth Neoplasms; Dog Diseases; Skin Neoplasms
PubMed: 38562982
DOI: No ID Found -
Journal of Controlled Release :... May 2024Local and long-lasting administration of potent chemotherapeutics is a promising therapeutic intervention to increase the efficiency of chemotherapy of hard-to-treat...
Local and long-lasting administration of potent chemotherapeutics is a promising therapeutic intervention to increase the efficiency of chemotherapy of hard-to-treat tumors such as the most lethal brain tumors, glioblastomas (GBM). However, despite high toxicity for GBM cells, potent chemotherapeutics such as gemcitabine (Gem) cannot be widely implemented as they do not efficiently cross the blood brain barrier (BBB). As an alternative method for continuous administration of Gem, we here operate freestanding iontronic pumps - "GemIPs" - equipped with a custom-synthesized ion exchange membrane (IEM) to treat a GBM tumor in an avian embryonic in vivo system. We compare GemIP treatment effects with a topical metronomic treatment and observe that a remarkable growth inhibition was only achieved with steady dosing via GemIPs. Daily topical drug administration (at the maximum dosage that was not lethal for the embryonic host organism) did not decrease tumor sizes, while both treatment regimes caused S-phase cell cycle arrest and apoptosis. We hypothesize that the pharmacodynamic effects generate different intratumoral drug concentration profiles for each technique, which causes this difference in outcome. We created a digital model of the experiment, which proposes a fast decay in the local drug concentration for the topical daily treatment, but a long-lasting high local concentration of Gem close to the tumor area with GemIPs. Continuous chemotherapy with iontronic devices opens new possibilities in cancer treatment: the long-lasting and highly local dosing of clinically available, potent chemotherapeutics to greatly enhance treatment efficiency without systemic side-effects. SIGNIFICANCE STATEMENT: Iontronic pumps (GemIPs) provide continuous and localized administration of the chemotherapeutic gemcitabine (Gem) for treating glioblastoma in vivo. By generating high and constant drug concentrations near the vascularized growing tumor, GemIPs offer an efficient and less harmful alternative to systemic administration. Continuous GemIP dosing resulted in remarkable growth inhibition, superior to daily topical Gem application at higher doses. Our digital modelling shows the advantages of iontronic chemotherapy in overcoming limitations of burst release and transient concentration profiles, and providing precise control over dosing profiles and local distribution. This technology holds promise for future implants, could revolutionize treatment strategies, and offers a new platform for studying the influence of timing and dosing dependencies of already-established drugs in the fight against hard-to-treat tumors.
Topics: Animals; Gemcitabine; Deoxycytidine; Brain Neoplasms; Glioblastoma; Chick Embryo; Apoptosis; Cell Line, Tumor; Humans; Antineoplastic Agents; Administration, Metronomic
PubMed: 38548064
DOI: 10.1016/j.jconrel.2024.03.044 -
Frontiers in Oncology 2024
PubMed: 38482207
DOI: 10.3389/fonc.2024.1385766 -
Current Oncology Reports Apr 2024This review describes the most relevant studies found in the scientific literature regarding metronomic chemotherapy (MCT) in the geriatric oncology population to... (Review)
Review
PURPOSE OF REVIEW
This review describes the most relevant studies found in the scientific literature regarding metronomic chemotherapy (MCT) in the geriatric oncology population to support its use as a feasible treatment of care in the frail elderly patients.
RECENT FINDINGS
Recent years have seen a reevaluation of cancer chemotherapeutic drugs and MCT is an emerging schedule in phase II and III clinical trials. Ageing is one of the risk factors for the development of cancer, the incidence of whom increases dramatically in people who live longer. To date, standard oncological protocols involve chemotherapeutic drugs in short cycles of therapy at the maximum tolerated dose (MTD). Although these therapeutic regimens may be successful, they can cause important adverse drug reactions, especially in elderly or frail patients. MCT is a different modality of delivery of chemotherapeutic drugs (frequent low dose for prolonged time) and it looks at the overcoming of the limitations and disadvantages of MTD, in particular the toxicity aspect. We reviewed the experience of clinicians who have used MCT in clinical trials enrolling elderly patients with different cancer types.
Topics: Humans; Aged; Antineoplastic Agents; Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38448722
DOI: 10.1007/s11912-024-01505-w