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Expert Opinion on Investigational Drugs Jul 2009Significant advances in the diagnosis and treatment of brain tumors have been made through better imaging, surgical techniques and advances in radiation therapy.... (Review)
Review
Significant advances in the diagnosis and treatment of brain tumors have been made through better imaging, surgical techniques and advances in radiation therapy. However, the cure rate for most adult and pediatric brain tumor patients has not mirrored this success. Angiogenesis, the development of neovascularization, provides the required nutrients and oxygen to an expanding tumor and is controlled by a complex balance of proangiogenic cytokines and antiangiogenic factors. A series of new inhibitors of angiogenesis are now in clinical trials. Most of these rely on inhibiting tumor cell-mediated cytokines or blocking the activation of their cognate receptors. Cytotoxic chemotherapy, by contrast, targets dividing cells but can be modulated to attack dividing endothelial cells. This review will focus on the use of low-dose antiangiogenic (also called metronomic) chemotherapy to inhibit endothelial cell function and resultant neovascularization in the treatment of adult and pediatric brain tumors. By examining the biology and preclinical findings that led to the development of antiangiogenic/metronomic chemotherapy, clinical studies have been undertaken that support the role of this approach in the clinic, and have led to the introduction of a number of markers being used to better predict active combinations and appropriate patient populations.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Brain Neoplasms; Clinical Trials as Topic; Drug Administration Schedule; Humans; Neovascularization, Pathologic; Time Factors
PubMed: 19548852
DOI: 10.1517/13543780903025752 -
Indian Journal of Pediatrics Dec 2012Despite intensive research in the field of cancer, many pediatric cancers are still incurable with current treatment protocols. Repetitive administration of conventional... (Review)
Review
Despite intensive research in the field of cancer, many pediatric cancers are still incurable with current treatment protocols. Repetitive administration of conventional chemotherapy at maximal tolerated dose imposes many side effects that further limits the dosing and therefore decreases the anticancer effects. Usually limited options remain when a malignancy progresses after one or two lines of standard chemotherapy protocol. The goal of an oncologist at this point of time remains mainly palliative with an effort to halt the progression of cancer and improve quality of life. Metronomic chemotherapy is defined as the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks. It is thought this type of chemotherapy inhibits tumor growth primarily through anti-angiogenic mechanisms, promoting apoptosis and immune- surveillance.
Topics: Administration, Metronomic; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Disease Progression; Humans; Neoplasms; Neovascularization, Pathologic; Pediatrics
PubMed: 22544675
DOI: 10.1007/s12098-012-0759-z -
Clinical & Translational Oncology :... Feb 2007Conventional cytotoxic anticancer chemotherapeutic drugs were developed with the intent of treating cancer by direct killing or inhibition of growth of cycling tumour... (Review)
Review
Conventional cytotoxic anticancer chemotherapeutic drugs were developed with the intent of treating cancer by direct killing or inhibition of growth of cycling tumour cells. Recently, however, there has been considerable interest in the notion of exploiting such drugs as angiogenesis inhibitors. The rationale is based on the fact that virtually all classes of cancer chemotherapeutic drugs are designed to damage DNA or disrupt microtubules of dividing cells, and endothelial cell division takes place during new blood vessel formation, including tumour angiogenesis. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses, known as "metronomic chemotherapy", increases the putative antiangiogenic activity of certain drugs. Metronomic chemotherapy refers to the chronic administration of comparatively low doses of cytotoxic drugs at close, regular intervals, with no prolonged drug-free interruptions. The advantage of this strategy is lower toxicity and risk of emergence of drug-resistant tumour cells than conventional administration. This review describes the possible antiangiogenesis basis of this therapeutic strategy, the experimental studies published and the recent clinical studies that explore this less toxic schedule.
Topics: Angiogenesis Inhibitors; Drug Administration Schedule; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 17329220
DOI: 10.1007/s12094-007-0018-3 -
Clinical and Experimental Medicine Feb 2021Metronomic chemotherapy has shown promising antitumor activity in a number of malignancies. We previously reported a phase II clinical trial of metronomic UFT (a...
Metronomic chemotherapy has shown promising antitumor activity in a number of malignancies. We previously reported a phase II clinical trial of metronomic UFT (a 5-fluorouracil prodrug; 100 mg/twice per day p.o.) and cyclophosphamide (CTX; 500 mg/m i.v. bolus on day 1 and then 50 mg/day p.o.) plus celecoxib (200 mg/twice a day p.o.) in 38 patients with advanced refractory gastrointestinal tumors. The mechanisms of action of metronomic chemotherapy include inhibition of angiogenesis, direct cytotoxic effects on cancer cells, and, at least for drugs such as CTX, activation of the immune system. To further evaluate the latter, we carried out an immune system multiplex 14-cytokine profiling of plasma samples that were available (for day 0, day 28, and day 56) from 31 of the 38 patients in the above-noted clinical trial. Our results show that pre-treatment plasma-level cutoffs of interferon gamma (> 12.84 pg/ml), sCD40L (< 2168 pg/ml), interferon alpha 2 (> 55.11 pg/ml), and IL-17a (< 15.1 pg/ml) were predictive markers for those patients with better progression-free survival (p < .05 for each cytokine). After 28 days of metronomic therapy, the plasma levels of sCD40L, IL-17a, and IL-6 (< 130 pg/ml) could serve as predictors of improved progression-free survival, as could levels interferon gamma and sCD40L after 56 days of therapy. We observed minimal changes in cytokine profiles, from baseline, as a consequence of the metronomic therapy, with the exception of an elevation of IL-6 and IL-8 levels 28 days (and 56 days) after treatment started (p < 0.05). Our results indicate that a selective cytokine elevation involves IL-6 and IL-8, following metronomic chemotherapy administration. In addition, interferon gamma and sCD40L may be potential biomarkers for gastrointestinal cancer patients that are likely to benefit from metronomic chemotherapy. Our study contributes to our understanding of the mechanisms of action of metronomic chemotherapy, and the cytokine profiling we describe may guide future selection of gastrointestinal cancer patients for UFT/CTX/celecoxib combination metronomic chemotherapy.
Topics: Administration, Metronomic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cytokines; Follow-Up Studies; Gastrointestinal Neoplasms; Humans; Prognosis; Survival Rate
PubMed: 33048259
DOI: 10.1007/s10238-020-00666-9 -
Archives de Pediatrie : Organe Officiel... Aug 2009Angiogenesis is crucial for the growth of cancer. As such, it has become an established target in fighting cancer. Metronomic chemotherapy-the chronic administration of... (Review)
Review
Angiogenesis is crucial for the growth of cancer. As such, it has become an established target in fighting cancer. Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks-is a potential novel approach to controlling advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has the property of killing resistant cancer cells while significantly reducing undesirable toxic side effects. We review the data regarding the use of metronomic chemotherapy in children with cancer and discuss its potential uses and limits.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Child; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Neoplasms; Treatment Outcome
PubMed: 19446445
DOI: 10.1016/j.arcped.2009.03.019 -
Theranostics 2024Over the past two decades, metronomic chemotherapy has gained considerable attention and has demonstrated remarkable success in the treatment of cancer. Through chronic... (Review)
Review
Over the past two decades, metronomic chemotherapy has gained considerable attention and has demonstrated remarkable success in the treatment of cancer. Through chronic administration and low-dose regimens, metronomic chemotherapy is associated with fewer adverse events but still effectively induces disease control. The identification of its antiangiogenic properties, direct impact on cancer cells, immunomodulatory effects on the tumour microenvironment, and metabolic reprogramming ability has established the intrinsic multitargeted nature of this therapeutic approach. Recently, the utilization of metronomic chemotherapy has evolved from salvage treatment for metastatic disease to adjuvant maintenance therapy for high-risk cancer patients, which has been prompted by the success of several substantial phase III trials. In this review, we delve into the mechanisms underlying the antitumour effects of metronomic chemotherapy and provide insights into potential combinations with other therapies for the treatment of various malignancies. Additionally, we discuss health-economic advantages and candidates for the utilization of this treatment option.
Topics: Humans; Administration, Metronomic; Neoplasms; Tumor Microenvironment; Angiogenesis Inhibitors; Antineoplastic Agents; Animals; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38948068
DOI: 10.7150/thno.95619 -
Journal of Pediatric Hematology/oncology Mar 2023Burkitt lymphoma (BL) is an aggressive type of non-Hodgkin lymphoma (NHL). With high-dose combination chemotherapy, cure rates are excellent. Treatment for HIV-positive...
Burkitt lymphoma (BL) is an aggressive type of non-Hodgkin lymphoma (NHL). With high-dose combination chemotherapy, cure rates are excellent. Treatment for HIV-positive BL is similar to that for HIV-negative BL. Offering long-term intensive chemotherapy is difficult in resource-limited settings. Oral metronomic chemotherapy, though in vogue as a treatment modality, has limited evidence of its efficacy in HIV-positive BL. Here, we present the case of a child who was diagnosed with BL and HIV and administered metronomic chemotherapy, and also review the literature on the role of metronomic chemotherapy in non-Hodgkin lymphoma with and without HIV.
Topics: Child; Humans; Burkitt Lymphoma; Antineoplastic Combined Chemotherapy Protocols; HIV Infections
PubMed: 36161878
DOI: 10.1097/MPH.0000000000002547 -
Seminars in Cancer Biology Dec 2015Oncology has benefited from an increasingly growing number of groundbreaking innovations over the last decade. Targeted therapies, biotherapies, and the most recent... (Review)
Review
Oncology has benefited from an increasingly growing number of groundbreaking innovations over the last decade. Targeted therapies, biotherapies, and the most recent immunotherapies all contribute to increase the number of therapeutic options for cancer patients. Consequently, substantial improvements in clinical outcomes for some disease with dismal prognosis such as lung carcinoma or melanoma have been achieved. Of note, the latest innovations in targeted therapies or biotherapies do not preclude the use of standard cytotoxic agents, mostly used in combination. Importantly, and despite the rise of bioguided (a.k.a. precision) medicine, the administration of chemotherapeutic agents still relies on the maximum tolerated drug (MTD) paradigm, a concept inherited from theories conceptualized nearly half a century ago. Alternative dosing schedules such as metronomic regimens, based upon the repeated and regular administration of low doses of chemotherapeutic drugs, and adaptive therapy (i.e. modulating the dose and frequency of cytotoxics administration to control disease progression rather than eradicate it at all cost) have emerged as possible strategies to improve response rates while reducing toxicities. The recent changes in paradigm in the way we theorize cancer biology and evolution, metastatic spreading and tumor ecology, alongside the recent advances in the field of immunotherapy, have considerably strengthened the interest for these alternative approaches. This paper aims at reviewing the recent evolutions in the field of theoretical biology of cancer and computational oncology, with a focus on the consequences these changes have on the way we administer chemotherapy. Here, we advocate for the development of model-guided strategies to refine doses and schedules of chemotherapy administration in order to achieve precision medicine in oncology.
Topics: Administration, Metronomic; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Models, Theoretical; Neoplasms; Precision Medicine
PubMed: 26361213
DOI: 10.1016/j.semcancer.2015.09.002 -
Biomarkers in Medicine 2014Low-dose metronomic (LDM) chemotherapy is a beneficial and very well-tolerated form of chemotherapy utilization characterized by the frequent and uninterrupted... (Review)
Review
Low-dose metronomic (LDM) chemotherapy is a beneficial and very well-tolerated form of chemotherapy utilization characterized by the frequent and uninterrupted administration of low doses of conventional chemotherapeutic agents over prolonged periods of time. While patients resistant to standard maximum tolerated dose (MTD) chemotherapy may still benefit from LDM chemotherapy, there is a lack of predictive markers of response to LDM chemotherapy. We searched the MEDLINE, EMBASE, CENTRAL and PubMed databases for correlative studies conducted as part of LDM chemotherapy trials in order to identify the most promising biomarker candidates. Given the antiangiogenic properties of LDM chemotherapy, angiogenesis-related biomarkers were most commonly studied. However, significant correlations between angiogenesis-related biomarkers and study end points were rare and variable, even so far as biomarkers correlating positively with an end point in some studies and negatively with the same end point in other studies. Pursuing biomarkers outside the angiogenesis field may be more promising.
Topics: Administration, Metronomic; Biomarkers, Pharmacological; Humans; MEDLINE; Maximum Tolerated Dose
PubMed: 25224945
DOI: 10.2217/bmm.14.14 -
Cancer Investigation Feb 2023The combination of low-dose methotrexate and celecoxib as metronomic chemotherapy (MCT) is a novel therapy, believed to act by modulating the immune response, inhibiting... (Review)
Review
The combination of low-dose methotrexate and celecoxib as metronomic chemotherapy (MCT) is a novel therapy, believed to act by modulating the immune response, inhibiting angiogenesis and its cytotoxic action, though the exact mechanism of action is unclear. Clinically, MCT was found to be very effective in delaying tumor progression in patients with head and neck squamous cell carcinoma in both curative and palliative settings. This review was aimed to give a brief insight into the mechanism of action and potential molecular alterations of MCT in the treatment of oral cancers taking into consideration the various in vivo and in vitro studies.
Topics: Humans; Celecoxib; Squamous Cell Carcinoma of Head and Neck; Methotrexate; Carcinoma, Squamous Cell; Mouth Neoplasms; Head and Neck Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36269850
DOI: 10.1080/07357907.2022.2139840