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Cancer Letters Aug 2017We present a rationale for further clinical development and assessment of metronomic chemotherapy on the basis of unexpected results obtained in translational mouse... (Review)
Review
We present a rationale for further clinical development and assessment of metronomic chemotherapy on the basis of unexpected results obtained in translational mouse models of cancer involving treatment of advanced metastatic disease. Historically, mouse cancer therapy models have been dominated by treating established primary tumors or early stage low volume microscopic disease. Treatment of primary tumors is also almost always the case when using genetically engineered mouse models (GEMMs) of cancer or patient-derived xenografts (PDXs). Studies using such models, and others including transplanted cell lines, often yield highly encouraging results which are seldom recapitulated in the clinic, especially when assessed in randomized phase III clinical trials. While there are likely many different reasons for this discrepancy, one is likely the failure to recapitulate treatment of advanced visceral metastatic disease in mice. With this gap in mind, we have developed a number of models of metastatic human tumor xenografts (and more recently, of mouse tumors in syngeneic immunocompetent mice). A pattern of response we have observed with various targeted agents, e.g. VEGF pathway targeting antiangiogenic drugs or trastuzumab, is effective when treating primary tumors in contrast to a complete or severely reduced lack of such efficacy when treating advanced metastatic disease. Interestingly, an exception to this pattern has been observed using various continuous low-dose metronomic chemotherapy regimens, where counterintuitively, superior responses are observed in the metastatic setting, as well as superiority or equivalence of metronomic chemotherapy over standard maximum tolerated dose (MTD) chemotherapy, with lesser toxicity. The basis for these encouraging results may be related to the multiple mechanisms responsible for the anti-tumor effects and longer duration of metronomic chemotherapy regimens made possible by lesser toxicity. These include antiangiogenesis, stimulation of the immune system, stromal cell targeting in tumors, and possibly direct tumor cell targeting, including targeting cancer stem cells (CSCs). In addition, metronomic chemotherapy regimens minimize or even eliminate the problem of chemotherapy-induced host responses that may actually secondarily promote tumor growth and malignancy after causing an initial and beneficial anti-tumor response. We suggest that future preclinical studies of metronomic chemotherapy should be concentrated in the following areas: i) further comparative assessment of anti-tumor efficacy in primary vs metastatic treatment settings; ii) rigorous comparative assessment of conventional MTD chemotherapy vs metronomic chemotherapy using the same agent; iii) assessment of potential predictive biomarkers for metronomic chemotherapy, and methods to determine optimal biologic dose and schedule; and iv) a further detailed assessment of the potential of different chemotherapy drugs administered using MTD or metronomic regimens on stimulating or suppressing components of the innate or adaptive immune systems.
Topics: Administration, Metronomic; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Humans; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Neovascularization, Pathologic; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 28202353
DOI: 10.1016/j.canlet.2017.02.005 -
International Journal of Molecular... Oct 2019Low dose metronomic chemotherapy (MC) is becoming a mainstream treatment for cancer in veterinary medicine. Its mechanism of action is anti-angiogenesis by lowering... (Review)
Review
Low dose metronomic chemotherapy (MC) is becoming a mainstream treatment for cancer in veterinary medicine. Its mechanism of action is anti-angiogenesis by lowering vascular endothelial growth factor (VEGF) and increasing trombospondin-1 (TSP1). It has also been adopted as a compassionate treatment in very advanced human cancer. However, one of the main limitations of this therapy is its short-term effectiveness: 6 to 12 months, after which resistance develops. pH-centered cancer treatment (pHT) has been proposed as a complementary therapy in cancer, but it has not been adopted or tested as a mainstream protocol, in spite of existing evidence of its advantages and benefits. Many of the factors directly or indirectly involved in MC and anti-angiogenic treatment resistance are appropriately antagonized by pHT. This led to the testing of an association between these two treatments. Preliminary evidence indicates that the association of MC and pHT has the ability to reduce anti-angiogenic treatment limitations and develop synergistic anti-cancer effects. This review will describe each of these treatments and will analyze the fundamentals of their synergy.
Topics: Administration, Metronomic; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Drug Synergism; Humans; Hydrogen-Ion Concentration; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A
PubMed: 31683667
DOI: 10.3390/ijms20215438 -
Cancer Letters Sep 2018Tumor dormancy is the ability of cancer cells to survive in a non-proliferating state. This condition can depend on three main mechanisms: cell cycle arrest (quiescence... (Review)
Review
Tumor dormancy is the ability of cancer cells to survive in a non-proliferating state. This condition can depend on three main mechanisms: cell cycle arrest (quiescence or cell dormancy), immunosurveillance (immunologic dormancy), or lack of functional blood vessels (angiogenic dormancy). In particular, under angiogenic dormancy, cancer cell proliferation is counterbalanced by apoptosis owing to poor vascularization, impeding tumor mass expansion beyond a microscopic size, with an asymptomatic and non-metastatic state. Tumor vasculogenic or non-angiogenic switch is essential to promote escape from tumor dormancy, leading to tumor mass proliferation and metastasis. In avascular lesions angiogenesis process results blocked from the equilibrium between pro- and anti-angiogenic factors, such as vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1), respectively. The angiogenic switch mainly depends on the disruption of this balance, in favor of pro-angiogenic factors, and on the recruitment of circulating endothelial progenitors (CEPs) that promote the formation of new blood vessels. Metronomic chemotherapy, the regular intake of doses able to sustain low but active concentrations of chemotherapeutic drugs during protracted time periods, is an encouraging therapeutic approach that has shown to upregulate anti-angiogenic factors such as TSP-1 and decline pro-angiogenic factors such as VEGF, suppressing the proangiogenic cells such as CEPs. In this perspective, metronomic chemotherapy may be one of the available therapeutic approaches capable to modulate favorably the angiogenic tumor dormancy, but further research is essential to better define this particular characteristic.
Topics: Administration, Metronomic; Animals; Antineoplastic Agents; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 29885517
DOI: 10.1016/j.canlet.2018.06.002 -
Veterinary and Comparative Oncology Mar 2018The era of chemotherapy, which started in the middle of the last century, has been ruled by the routine use of dose-intense protocols, based on the "maximum-tolerated... (Review)
Review
The era of chemotherapy, which started in the middle of the last century, has been ruled by the routine use of dose-intense protocols, based on the "maximum-tolerated dose" concept. By promoting a balance between patient's quality of life and the goal of rapidly killing as many tumour cells as possible, these protocols still play a prominent role in veterinary oncology. However, with the opening of a new millennium, metronomic chemotherapy (MC) started to be considered a possible alternative to traditional dose-intense chemotherapy. Characterized by a long-term daily administration of lower doses of cytotoxic drugs, this new modality stands out for its unique combination of effects, namely on neovascularization, immune response and tumour dormancy. This article reviews the rationale for treatment with MC, its mechanism of action and the main studies conducted in veterinary medicine, and discusses the key challenges yet to be solved.
Topics: Administration, Metronomic; Animals; Antineoplastic Agents; Dog Diseases; Dogs; Neoplasms
PubMed: 28317239
DOI: 10.1111/vco.12309 -
Lancet (London, England) Jul 2021Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical... (Randomized Controlled Trial)
Randomized Controlled Trial
Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.
BACKGROUND
Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options.
METHODS
This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111.
FINDINGS
Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group.
INTERPRETATION
The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma.
FUNDING
The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation.
TRANSLATION
For the Chinese translation of the abstract see Supplementary Materials section.
Topics: Administration, Metronomic; Adult; Aged; Antimetabolites, Antineoplastic; Capecitabine; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Humans; Male; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Young Adult
PubMed: 34111416
DOI: 10.1016/S0140-6736(21)01123-5 -
Cancer Letters Aug 2017Metronomic chemotherapy refers to the frequent administration of chemotherapy at relatively low, minimally toxic doses without prolonged treatment interruptions.... (Review)
Review
Metronomic chemotherapy refers to the frequent administration of chemotherapy at relatively low, minimally toxic doses without prolonged treatment interruptions. Different from conventional or maximum-tolerated-dose chemotherapy which aims at an eradication of all malignant cells, in a metronomic dosing the goal often lies in the long-term management of the disease when eradication proves elusive. Mathematical modeling and subsequent analysis (theoretical as well as numerical) have become an increasingly more valuable tool (in silico) both for determining conditions under which specific treatment strategies should be preferred and for numerically optimizing treatment regimens. While elaborate, computationally-driven patient specific schemes that would optimize the timing and drug dose levels are still a part of the future, such procedures may become instrumental in making chemotherapy effective in situations where it currently fails. Ideally, mathematical modeling and analysis will develop into an additional decision making tool in the complicated process that is the determination of efficient chemotherapy regimens. In this article, we review some of the results that have been obtained about metronomic chemotherapy from mathematical models and what they infer about the structure of optimal treatment regimens.
Topics: Administration, Metronomic; Antineoplastic Agents; Computer Simulation; Decision Support Techniques; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Models, Statistical; Models, Theoretical; Neoplasms; Numerical Analysis, Computer-Assisted; Patient Selection; Time Factors; Treatment Outcome; Tumor Microenvironment
PubMed: 28323033
DOI: 10.1016/j.canlet.2017.03.021 -
BMC Cancer Oct 2015In the era of personalized medicine, head and neck squamous cell carcinoma (HNSCC) represents a critical oncologic topic. Conventional chemotherapy regimens consist of... (Review)
Review
In the era of personalized medicine, head and neck squamous cell carcinoma (HNSCC) represents a critical oncologic topic. Conventional chemotherapy regimens consist of drugs administration in cycles near or at the maximum tolerated dose (MDT), followed by a long drug-free period to permit the patient to recover from acute toxicities. Despite this strategy is successful in controlling the cancer process at the beginning, a significant number of HNSCC patients tend to recurred or progress, especially those patients with locally advanced or metastatic disease. The repertoire of drugs directed against tumor cells has greatly increased and metronomic chemotherapy (MC) could be an effective treatment option.It is the purpose of this article to review the concept of MC and describe its potential use in HNSCC. We provide an update of ongoing progress and current challenges related to this issue.
Topics: Administration, Metronomic; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Clinical Trials as Topic; Drug Evaluation, Preclinical; Head and Neck Neoplasms; Humans; Squamous Cell Carcinoma of Head and Neck; Treatment Outcome
PubMed: 26459302
DOI: 10.1186/s12885-015-1705-z -
European Journal of Cancer (Oxford,... Nov 2013Low-dose metronomic (LDM) chemotherapy, the frequent and continuous use of low doses of conventional chemotherapeutics, is an emerging alternative to conventional... (Meta-Analysis)
Meta-Analysis Review
Low-dose metronomic (LDM) chemotherapy, the frequent and continuous use of low doses of conventional chemotherapeutics, is an emerging alternative to conventional chemotherapy. While promising tumour control rates and excellent safety profiles have been observed, there are no definitive phase III trial results. Furthermore, the selection of patients, drug dosages and dosing intervals is empirical. To systematically review the current state of knowledge regarding LDM chemotherapy, we searched the MEDLINE, EMBASE, CENTRAL and PubMed databases for fully published LDM chemotherapy trials. We calculated the relative dose-intensity (RDI, mg/m(2)/week) of each LDM regimen as compared to conventional maximum tolerated dose (MTD) dosages and the 'dosing-density' (DD, % of days with chemotherapy administration per cycle). Meta-regression was performed to examine factors associated with disease control rate (DCR; complete response (CR)+partial response (PR)+stable disease (SD)). Eighty studies involving mainly pretreated patients with advanced/metastatic breast (26.25%) and prostate (11.25%) cancers were retrieved. The most commonly used drug was cyclophosphamide (43%). LDM chemotherapy was frequently combined with other therapies (64.5%). Response rate (RR) and progression-free survival (PFS) were the most frequent primary end-points (24% and 19%). Mean RR was 26.03% (95% confidence interval (CI): 21.4-30.7), median PFS was 4.6months (interquartile range (IQR): 2.9-7.0) and mean DCR was 56.3% (95% CI: 50.9-61.6). RDI, DD and metronomic drug used were not associated with DCR. Grade 3/4 adverse events were rare (anaemia 7.78%, fatigue 13.4%). Thus, LDM therapy appears to be clinically beneficial and safe in a broad range of tumors. However, meta-regression analysis did not identify predictive factors of response.
Topics: Administration, Metronomic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease Progression; Disease-Free Survival; Female; Humans; Male; Prostatic Neoplasms; Remission Induction; Time Factors; Treatment Outcome
PubMed: 23880474
DOI: 10.1016/j.ejca.2013.06.038 -
Cancer Letters Aug 2017Drug resistance is a major problem in anticancer therapy. ATP-binding cassette (ABC) transporters have a role in the multidrug resistance. A new regimen of chemotherapy... (Review)
Review
Drug resistance is a major problem in anticancer therapy. ATP-binding cassette (ABC) transporters have a role in the multidrug resistance. A new regimen of chemotherapy has been proposed, called "metronomic chemotherapy". Metronomic chemotherapy is the frequent, regular administration of drug doses designed to maintain low, but active, concentrations of chemotherapeutic drugs over prolonged periods of time, without causing serious toxicities. Metronomic chemotherapy regimens were developed to optimize the antitumor efficacy of agents that target the tumor vasculature instead of tumor cells, and to reduce toxicity of antineoplastic drugs [1]. Nevertheless, recent studies revealed that ABC transporters are expressed at a higher level in the endothelium in the tumor. To avoid resistance to metronomic anti-angiogenic chemotherapy, ABC transporter inhibition of tumor endothelial cells may be a promising strategy. In this mini-review, we discuss the possible mechanism of resistance to metronomic chemotherapy from the viewpoint of tumor endothelial cell biology, focusing on ABC transporters.
Topics: ATP-Binding Cassette Transporters; Administration, Metronomic; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Endothelial Cells; Humans; Neoplasms
PubMed: 28216371
DOI: 10.1016/j.canlet.2017.02.006 -
Journal of Clinical Oncology : Official... Mar 2020Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes.
METHODS
Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach.
RESULTS
There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes.
CONCLUSION
Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.
Topics: Administration, Metronomic; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Breast Neoplasms; Cyclophosphamide; Dietary Supplements; Disease-Free Survival; Doxorubicin; Female; Humans; Middle Aged; Paclitaxel; Proportional Hazards Models; Vitamins
PubMed: 31855498
DOI: 10.1200/JCO.19.01203