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The Lancet. Oncology Nov 2019
Topics: Administration, Metronomic; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Erlotinib Hydrochloride; Humans; Methotrexate; Mouth Neoplasms; Progression-Free Survival
PubMed: 31564522
DOI: 10.1016/S1470-2045(19)30623-0 -
Biomaterials Jul 2022In conventional chemotherapy, maximum tolerated dose approach is considered as a first-line medication for cancer treatment in clinics. In contrast to the conventional...
In conventional chemotherapy, maximum tolerated dose approach is considered as a first-line medication for cancer treatment in clinics. In contrast to the conventional chemotherapy which has heavy tumor burdens arising from high dose treatment, metronomic chemotherapy (MCT) engages relatively low dose without drug-free breaks, and is recognized as a promising strategy for a long-term management of the disease. Although doxorubicin (DOX), an anthracycline anti-cancer drug, showed a potential of maintenance effect in vitro, further study on in vivo-relevant concentration to achieve tumor suppression with no toxicity is required to apply the MCT in clinicals. Therefore, the objective of this study was to identify an optimal MCT regimen of DOX by determining concentration-response relationships of tumor suppression (pharmacodynamic; PD) and cardiac toxicity (toxicodynamic; TD). Utilizing an oral DOX formulation complexed with deoxycholic acid (DOX/DOCA complex) which has enhanced bioavailability, physiologically-based pharmacokinetic (PBPK) model was linked to TD and PD models to generate drug profiles from the combined PK, TD, and PD parameters. The integrated model was validated for various scenarios of administration route, formulation, dose, and frequency. The established mathematical model facilitated calculations of adequate in vivo-relevant dosages and intervals, suggesting the optimum oral metronomic regimen of DOX. It is expected to serve as a useful guideline for the design and evaluation of oral DOX formulations in future preclinical/clinical studies.
Topics: Administration, Metronomic; Antibiotics, Antineoplastic; Doxorubicin; Humans; Models, Theoretical; Neoplasms
PubMed: 35617783
DOI: 10.1016/j.biomaterials.2022.121584 -
Annals of Oncology : Official Journal... Feb 2019Cancer immunotherapy has changed the standard of care for a subgroup of patients with advanced disease. Immune checkpoint blockade (ICB) in particular has shown improved... (Review)
Review
BACKGROUND
Cancer immunotherapy has changed the standard of care for a subgroup of patients with advanced disease. Immune checkpoint blockade (ICB) in particular has shown improved survival compared with previous standards of care for several tumor types. Although proven to be successful in more immunogenic tumors, ICB is still largely ineffective in patients with tumors that are not infiltrated by immune cells, the so-called cold tumors.
PATIENTS AND METHODS
This review describes the effects of different chemotherapeutic agents on the immune system and the potential value of these different types of chemotherapy as combination partners with ICB in patients with solid tumors. Both preclinical data and currently ongoing clinical trials were evaluated. In addition, we reviewed findings regarding different dosing schedules, including the effects of an induction phase and applying metronomic doses of chemotherapy.
RESULTS
Combining ICB with other treatment modalities may lead to improved immunological conditions in the tumor microenvironment and could thereby enhance the antitumor immune response, even in tumor types that are so far unresponsive to ICB monotherapy. Chemotherapy, that was originally thought to be solely immunosuppressive, can exert immunomodulatory effects which may be beneficial in combination with immunotherapy. Each chemotherapeutic drug impacts the tumor microenvironment differently, and in order to determine the most suitable combination partners for ICB it is crucial to understand these mechanisms.
CONCLUSION
Preclinical studies demonstrate that the majority of chemotherapeutic drugs has been shown to exert immunostimulatory effects, either by inhibiting immunosuppressive cells and/or activating effector cells, or by increasing immunogenicity and increasing T-cell infiltration. However, for certain chemotherapeutic agents timing, dose and sequence of administration of chemotherapeutic agents and ICB is important. Further studies should focus on determining the optimal drug combinations, sequence effects and optimal concentration-time profiles in representative preclinical models.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Checkpoints; Drug Therapy, Combination; Humans; Immunotherapy; Neoplasms; Prognosis; Tumor Microenvironment
PubMed: 30608567
DOI: 10.1093/annonc/mdy551 -
Expert Opinion on Pharmacotherapy Dec 2021
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Gastrointestinal Neoplasms; Humans
PubMed: 34165012
DOI: 10.1080/14656566.2021.1940953 -
Journal of Neuroendocrinology Oct 2022Neuroendocrine tumors (NETs) are more commonly slow-growing, therefore patients often receive chronic systemic therapies for tumor growth control and preservation of...
Neuroendocrine tumors (NETs) are more commonly slow-growing, therefore patients often receive chronic systemic therapies for tumor growth control and preservation of quality of life. Metronomic chemotherapy (mCT) is in line with this goal as it leads to stabilization of tumor growth over time without severe systemic toxicity. This is a retrospective analysis of patients with metastatic NETs receiving metronomic capecitabine (mCAP) or temozolomide (mTEM), at a NET-referral center. The aims of the study were to explore activity and safety of mCT and relationships between some characteristics of the patient population and clinical outcomes. Among a total of 67 patients with metastatic well or moderately differentiated (W/M-D) NETs, mostly gastroenteropancreatic (GEP) and nonfunctioning, 1.2 years (95% CI: 0.8-1.8) median progression-free survival (mPFS), and 3.0 years (95% CI: 2.3-4.9) median overall survival (mOS) were observed. Disease control rate was 85%. Grade 3 adverse events occurred in 15% of patients in mCAP and 13% in mTEM, and were mostly hematological and gastrointestinal. At univariate and multivariate analysis none of the variables analyzed (treatment regimen, sex, age at diagnosis, site of primary tumor and metastases, number of previous mCT lines, baseline tumor status before mCT, Ki67 value) were significantly correlated to OS and PFS. Our retrospective study suggested that mCAP and mTEM can be active and well tolerated in patients with metastatic W/M-D NETs, irrespective of the primary site, site of metastases, line of treatment and baseline tumor status.
Topics: Humans; Neuroendocrine Tumors; Retrospective Studies; Quality of Life; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Capecitabine
PubMed: 36306196
DOI: 10.1111/jne.13189 -
Cancer Letters Mar 2017Metronomic administration of chemotherapy has long been recognized as having a different biological effect from maximal tolerated dose (MTD) administration. Preclinical...
Metronomic administration of chemotherapy has long been recognized as having a different biological effect from maximal tolerated dose (MTD) administration. Preclinical studies have demonstrated these differences quite elegantly and many clinical trials have also demonstrated reproducible activity albeit small, in varied solid malignancies even in patients who were heavily pretreated. However, the concept of metronomic chemotherapy has been plagued by lack of a clear definition resulting in the published literature that is rather varied and confusing. There is a need for a definition that is mechanism(s)-based allowing metronomics to be distinguished from standard MTD concept. With significant advances made in understanding cancer biology and biotechnology, it is now possible to attain that goal. What is needed is both a concerted effort and adequate funding to work towards it. This is the only way for the oncology community to determine how metronomic chemotherapy fits in the overall cancer management schema.
Topics: Administration, Metronomic; Antineoplastic Combined Chemotherapy Protocols; Humans; Neoplasms
PubMed: 28003122
DOI: 10.1016/j.canlet.2016.12.013 -
Lancet (London, England) Jul 2021
Topics: Chemotherapy, Adjuvant; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms
PubMed: 34111417
DOI: 10.1016/S0140-6736(21)01240-X -
Critical Reviews in Oncology/hematology Apr 2012Metronomic (low-dose, long-term and frequently administered) chemotherapy has attracted renewed interest for the past few years, in particular because of possible... (Review)
Review
Metronomic (low-dose, long-term and frequently administered) chemotherapy has attracted renewed interest for the past few years, in particular because of possible positive association with molecular targeted agents. Cyclophosphamide is the most widely-explored agent in such an approach. The main possible mechanisms of actions identified in preclinical models, whatever the histology of tumor, are the stimulation of the immune system and anti-angiogenic action. Retrospective studies and numerous phase II clinical trials have been published in diverse clinical settings, mainly in patients with highly pretreated advanced tumors. The tolerance seems to be acceptable; some objective responses have been reported. Nevertheless, the regimens were very heterogeneous, and most of these studies are not randomized. This makes it difficult to objectively evaluate the additional value of the metronomic administration of cyclophosphamide. Further clinical trials integrating translational research are necessary to better evaluate the clinical benefit of this promising approach.
Topics: Administration, Metronomic; Animals; Antineoplastic Agents, Alkylating; Clinical Trials as Topic; Cyclophosphamide; Dogs; Humans; Mice; Neoplasms; Sarcoma; Treatment Outcome
PubMed: 21641231
DOI: 10.1016/j.critrevonc.2011.04.009 -
The Veterinary Clinics of North... Sep 2014Cancer chemotherapy in dogs and cats has traditionally involved administration of chemotherapy agents at the maximum tolerated dose. Cytotoxic chemotherapy has an... (Review)
Review
Cancer chemotherapy in dogs and cats has traditionally involved administration of chemotherapy agents at the maximum tolerated dose. Cytotoxic chemotherapy has an acceptably low risk of serious toxicity, but an obligatory rest period must be included to allow for recovery of drug-sensitive normal cell populations. This rest period can also allow significant recovery of tumor cells. Metronomic chemotherapy is characterized by more frequent administration of lower doses of oral drugs and appears to halt or slow tumor progression through multiple mechanisms. This approach may be at least as effective as conventional chemotherapy with a lower risk of toxicity.
Topics: Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cat Diseases; Cats; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Neoplasms
PubMed: 25174901
DOI: 10.1016/j.cvsm.2014.05.003 -
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