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Cancers Aug 2023Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of "maintaining" tumor complete remission. This... (Review)
Review
Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of "maintaining" tumor complete remission. This paper aims to report an update of the RMS2005 trial, which demonstrated better survival for patients with high-risk localized rhabdomyosarcoma (RMS) when MC with vinorelbine and low-dose cyclophosphamide was added to standard chemotherapy, and to discuss the published experience on MC in RMS. In the RMS2005 study, the outcome for patients receiving MC vs. those who stopped the treatment remains superior, with a 5-year disease-free survival of 78.1% vs. 70.1% ( = 0.056) and overall survival of 85.0% vs. 72.4% ( = 0.008), respectively. We found seven papers describing MC in RMS, but only one randomized trial that did not demonstrate any advantage when MC with eight courses of trofosfamide/idarubicine alternating with trofosfamide/etoposide has been employed in high-risk RMS. The use of MC showed better results in comparison to high-dose chemotherapy in non-randomized studies, including metastatic patients, and demonstrated feasibility and tolerability in relapsed RMS. Many aspects of MC in RMS need to be investigated, including the best drug combination and the optimal duration. The ongoing EpSSG trial will try to answer some of these questions.
PubMed: 37568826
DOI: 10.3390/cancers15154012 -
Journal For Immunotherapy of Cancer Jan 2021Poly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib) are effective against BRCA-mutated cancers at/near maximum tolerated doses by trapping PARP-1 on damaged...
BACKGROUND
Poly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib) are effective against BRCA-mutated cancers at/near maximum tolerated doses by trapping PARP-1 on damaged chromatin, benefitting only small patient proportions. The benefits of targeting non-DNA repair aspects of PARP with metronomic doses remain unexplored.
METHODS
Colon epithelial cells or mouse or human bone marrow (BM)-derived-myeloid-derived suppressor cells (MDSCs) were stimulated to assess the effect of partial PARP-1 inhibition on inflammatory gene expression or immune suppression. Mice treated with azoxymethane/four dextran-sulfate-sodium cycles or mice bred into PARP-1 or treated with olaparib were used to examine the role of PARP-1 in colitis-induced or spontaneous colon cancer, respectively. Syngeneic MC-38 cell-based (microsatellite instability, MSI) or CT-26 cell-based (microsatellite stable, MSS) tumor models were used to assess the effects of PARP inhibition on host responses and synergy with anti-Programmed cell Death protein (PD)-1 immunotherapy.
RESULTS
Partial PARP-1 inhibition, via gene heterozygosity or a moderate dose of olaparib, protected against colitis-mediated/ -mediated intestinal tumorigenesis and -associated cachexia, while extensive inhibition, via gene knockout or a high dose of olaparib, was ineffective or aggravating. A sub-IC50-olaparib dose or PARP-1 heterozygosity was sufficient to block tumorigenesis in a syngeneic colon cancer model by modulating the suppressive function, but not intratumoral migration or differentiation, of MDSCs, with concomitant increases in intratumoral T cell function and cytotoxicity, as assessed by granzyme-B/interferon-γ levels. Adoptive transfer of WT-BM-MDSCs abolished the protective effects of PARP-1 heterozygosity. The mechanism of MDSC modulation involved a reduction in arginase-1/inducible nitric oxide synthase/cyclo-oxygenase-2, but independent of PARP-1 trapping on chromatin. Although a high-concentration olaparib or the high-trapping PARP inhibitor, talazoparib, activated stimulator of interferon gene (STING) in BRCA-proficient cells and induced DNA damage, sub-IC50 concentrations of either drug failed to induce activation of the dsDNA break sensor. STING expression appeared dispensable for MDSC suppressive function and was not strictly required for olaparib-mediated effects. Ironically, STING activation blocked human and mouse MDSC function with no additive effects with olaparib. A metronomic dose of olaparib was highly synergistic with anti-PD-1-based immunotherapy, leading to eradication of MSI or reduction of MSS tumors in mice.
CONCLUSIONS
These results support a paradigm-shifting concept that expands the utility of PARP inhibitor and encourage testing metronomic dosing of PARP inhibitor to enhance the efficacy of checkpoint inhibitor-based immunotherapies in cancer.
Topics: Administration, Metronomic; Animals; Azoxymethane; Cell Line, Tumor; Colitis; Colonic Neoplasms; Dextran Sulfate; Drug Synergism; Humans; Immune Checkpoint Inhibitors; Mice; Myeloid-Derived Suppressor Cells; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Xenograft Model Antitumor Assays
PubMed: 33495297
DOI: 10.1136/jitc-2020-001643 -
JAMA Oncology Dec 2023Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.
IMPORTANCE
Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.
OBJECTIVE
To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]).
DESIGN, SETTING, AND PARTICIPANTS
This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021.
INTERVENTIONS
Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine.
MAIN OUTCOMES AND MEASURES
The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety.
RESULTS
Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia.
CONCLUSIONS AND RELEVANCE
This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01356290.
Topics: Humans; Male; Child; Child, Preschool; Adolescent; Female; Medulloblastoma; Etoposide; Quality of Life; Administration, Metronomic; Brain Neoplasms; Cerebellar Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37883081
DOI: 10.1001/jamaoncol.2023.4437 -
Oncology Research and Treatment 2022As disease control and quality of life play a leading role in metastatic breast cancer (MBC), metronomic chemotherapy (MCT) is gaining popularity alongside conventional... (Review)
Review
BACKGROUND
As disease control and quality of life play a leading role in metastatic breast cancer (MBC), metronomic chemotherapy (MCT) is gaining popularity alongside conventional chemotherapy (CCT) and targeted therapies.
SUMMARY
MCT, defined as continuous administration of low-dose chemotherapeutic agents, is accepted as a therapy that exerts its effects via immunomodulation, anti-angiogenesis and direct cytotoxic effects. Oral administration of MCT is safe, easy to handle, and allows for flexible drug dosing. Dose accumulations associated with non-tolerable side effects are rare, so the medication can be administered for longer periods of time. Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic disease resistant to endocrine-based therapy and not requiring rapid tumor response are generally suitable for MCT. However, MCT may also be promising in patients with triple-negative and HER2-positive tumors without aggressive disease who prefer a lower toxicity profile compared to CCT. The most commonly used agents are cyclophosphamide (CTX), methotrexate (MTX), capecitabine (CAPE), and vinorelbine (VRL), whereby a combination of agents is frequently applied. Key Messages: Based on the growing body of evidence, MCT can be considered as a suitable treatment option in selected MBC patients. Nevertheless, there is an urgent need for randomized controlled trials comparing MCT with CCT, but also with best supportive care. Due to the multimodal mechanisms of action, the combination with targeted and immunological therapies may represent a new promising approach for the treatment of MBC.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cyclophosphamide; Female; Humans; Quality of Life; Receptor, ErbB-2
PubMed: 34794154
DOI: 10.1159/000520236 -
Cancers Apr 2023Increasing evidence pinpoints metronomic chemotherapy, a frequent and low dose drug administration with no prolonged drug-free intervals, as a potential tool to fight... (Review)
Review
Increasing evidence pinpoints metronomic chemotherapy, a frequent and low dose drug administration with no prolonged drug-free intervals, as a potential tool to fight certain types of cancers. The primary identified targets of metronomic chemotherapy were the tumor endothelial cells involved in angiogenesis. After this, metronomic chemotherapy has been shown to efficiently target the heterogeneous population of tumor cells and, more importantly, elicit the innate and adaptive immune system reverting the "cold" to "hot" tumor immunologic phenotype. Although metronomic chemotherapy is primarily used in the context of a palliative setting, with the development of new immunotherapeutic drugs, a synergistic therapeutic role of the combined metronomic chemotherapy and immune checkpoint inhibitors has emerged at both the preclinical and clinical levels. However, some aspects, such as the dose and the most effective scheduling, still remain unknown and need further investigation. Here, we summarize what is currently known of the underlying anti-tumor effects of the metronomic chemotherapy, the importance of the optimal therapeutic dose and time-exposure, and the potential therapeutic effect of the combined administration of metronomic chemotherapy with checkpoint inhibitors in preclinical and clinical settings.
PubMed: 37173937
DOI: 10.3390/cancers15092471 -
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 -
Cancer Letters Nov 2023Translational research and the development of targeted therapies have transformed the therapeutic landscape in epithelial ovarian cancer over the last decade. However,...
Translational research and the development of targeted therapies have transformed the therapeutic landscape in epithelial ovarian cancer over the last decade. However, recurrent ovarian cancer continues to pose formidable challenges to therapeutic interventions, necessitating innovative strategies to optimize treatment outcomes. Current research focuses on the development of pharmaceuticals that target potential resistance pathways to DNA repair pathways. However, the cost and toxicity of some of these therapies are prohibitive and majority of patients lack access to clinical trials. Metronomic chemotherapy, characterized by the continuous administration of low doses of chemotherapeutic agents without long treatment breaks, has emerged as a promising approach with potential implications beyond recurrent setting. It acts primarily by inhibition of angiogenesis and activation of host immune system. We here review the mechanism of action of metronomic chemotherapy, as well as its current role, limitations, and avenues for further research in the management of epithelial ovarian cancer.
Topics: Female; Humans; Angiogenesis Inhibitors; Carcinoma, Ovarian Epithelial; Administration, Metronomic; Neoplasm Recurrence, Local; Ovarian Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37923056
DOI: 10.1016/j.canlet.2023.216469 -
Pharmaceutics Apr 2023Cancer-related death is a significant health and economic burden worldwide, and some conventional chemotherapy is associated with limited effectiveness in completely... (Review)
Review
Cancer-related death is a significant health and economic burden worldwide, and some conventional chemotherapy is associated with limited effectiveness in completely curing various cancers, severe adverse effects, and destruction of healthy cells. To overcome the complications associated with conventional treatment, metronomic chemotherapy (MCT) is extensively suggested. In this review, we aim to highlight the importance of MCT over conventional chemotherapeutic approach with emphasis on nanoformulations-based MCT, their mechanism, challenges, recent advances, and future perspectives. Nanoformulations-based MCT revealed remarkable antitumor activity in both preclinical and clinical settings. For example, the metronomic scheduling of oxaliplatin-loaded nanoemulsion and polyethylene glycol-coated stealth nanoparticles incorporating paclitaxel were proven very effective in tumor-bearing mice and rats, respectively. Additionally, several clinical studies have demonstrated the benefit of MCT with acceptable tolerance. Moreover, metronomic might be a promising treatment strategy for improving cancer care in low- and middle-income nations. However, an appropriate alternative to a metronomic regimen for an individual ailment, suitable combinational delivery and scheduling, and predictive biomarkers are certain parts that remain unanswered. Further clinical-based comparative research studies are mandatory to be performed before entailing this treatment modality in clinical practice as alternative maintenance therapy or in place of transferring to therapeutic management.
PubMed: 37111677
DOI: 10.3390/pharmaceutics15041192 -
Cancers Oct 2022Medulloblastoma (MB) recurrence is usually incurable despite intensive therapy including high-dose chemotherapy. An evolving alternative approach to conventional...
Medulloblastoma (MB) recurrence is usually incurable despite intensive therapy including high-dose chemotherapy. An evolving alternative approach to conventional chemotherapy aims at interfering with tumor angiogenesis at different levels. We report on a novel combinatorial metronomic antiangiogenic approach. The study is a retrospective observational study of 29 consecutive patients with first or multiple recurrences prospectively treated according to the MEMMAT strategy ("MEMMAT-like") before the formal protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) started. The study period was 11/2006 to 06/2016. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by IV bevacizumab and intraventricular therapy consisting of alternating etoposide and liposomal cytarabine. Median overall survival (OS) after recurrence for the whole group was 29.5 months, OS was 48.3 ± 9.3% at three years and 34.5 ± 8.8% at five years, and progression-free survival was 42.0 ± 9.5% at three years and 29.4 ± 9% at five years. As of 07/2022, 9/29 patients are alive 86 to 164 months after the recurrence that prompted the "MEMMAT-like" therapy. Treatment was primarily out-patient and generally well-tolerated. Toxicities did occur but were manageable. In conclusion, antiangiogenic therapy according to the MEMMAT strategy increased median OS of patients with recurrent MB and may lead to long-term survival. Adherence to the protocol, including intraventricular therapy, appears important.
PubMed: 36291912
DOI: 10.3390/cancers14205128 -
Current Opinion in Oncology Jan 2021In this article, we focus on the current and future treatment options for adrenocortical carcinoma (ACC). (Review)
Review
PURPOSE OF REVIEW
In this article, we focus on the current and future treatment options for adrenocortical carcinoma (ACC).
RECENT FINDINGS
Radical surgery remains the only curative treatment for ACC. Recent reports showed a longer overall survival (OS) in patients with high risk of recurrence treated with adjuvant mitotane; the time in target range (14-20 mg/l) is related to low risk of relapse both in adjuvant and in palliative setting. In patients who experience disease progression after etoposide, doxorubicin, cisplatin with mitotane (EDP-M), gemcitabine and metronomic capecitabine, or the less used streptozotocin, represent a second-line chemotherapy option. Temozolomide can be employed as a third-line chemotherapy. To date, unsatisfactory results have been obtained on the efficacy of targeted therapies. Clinical trials are ongoing to evaluate the efficacy of tyrosine kinase and immune checkpoint inhibitors.
SUMMARY
ACC is a rare disease with a poor prognosis. The main therapy is represented by radical surgery conducted by an expert surgeon. Adjuvant mitotane has to be started in patients with high risk of recurrence. In patients with inoperable disease, the scheme EDP-M is the most employed. Few data are available on second-line and third-line chemotherapy in patients with disease progression after EDP-M. Currently, the role of targeted therapies is under evaluation.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deoxycytidine; Humans; Mitotane; Randomized Controlled Trials as Topic; Gemcitabine
PubMed: 33186181
DOI: 10.1097/CCO.0000000000000695