Metronomic chemotherapy for non-metastatic triple negative breast cancer: Selection is the key

Triple negative breast cancer(TNBC) accounts for 15%-20% of all breast cancer, and is still defined as what it is not. Currently, TNBC is the only type of breast cancer for which there are no approved targeted therapies and maximum tolerated dose chemotherapy with taxanes and anthracycline-containing regimens is still the standard of care in both the neoadjuvant and adjuvant settings. In the last years, metronomic chemotherapy(MC) is being explored as an alternative to improve outcomes in TNBC. In the neoadjuvant setting, purely metronomic and hybrid approaches have been developed with the objective of increasing complete pathologic response(p CR) and prolonging disease free survival. These regimens proved to be very effective achieving pC R rates between 47%-60%, but at the cost of great toxicity. In the adjuvant setting, MC is used to intensify adjuvant chemotherapy and, more promisingly, as maintenance therapy for high-risk patients, especially those with no pC R after neoadjuvant chemotherapy. Considering the dismal prognosis of TNBC, any strategy that potentially improves outcomes, specially being the oral agents broadly available and inexpensive, should be considered and certainly warrants further exploration. Finally, the benefit of MC needs to be validated in properly designed clinical trials were the selection of the population is the key.

Combinations of vascular endothelial growth factor pathway inhibitors with metronomic chemotherapy:Rational and current status

Chemotherapy given in a metronomic manner can be administered with less adverse effects which are common with conventional schedules such as myelotoxicity and gastrointestinal toxicity and thus may be appropriate for older patients and patients with decreased performance status. Efficacy has been observed in several settings. An opportunity to improve the efficacy of metronomic schedules without significantly increasing toxicity presents with the addition of anti-angiogenic targeted treatments. These combinations rational stems from the understanding of the importance of angiogenesis in the mechanism of action of metronomic chemotherapy which may be augmented by specific targeting of the vascular endothelial growth factor(VEGF) pathway by antibodies or small tyrosine kinase inhibitors. Combinations of metronomic chemotherapy schedules with VEGF pathway targeting drugs will be discussed in this paper.

Low-Dose Metronomic Chemotherapy in Metastatic Breast Cancer: A Retrospective Analysis of 40 Patients

Purpose: Low-dose metronomic chemotherapy is an emergent treatment schedule in which low doses of cytotoxic agents are given orally continuously, with no or short drug-free intervals. In general, it provides better tolerance, especially in patients who have been previously exposed to other oncologic treatments, with a favorable cost-effectiveness profile. It is well known that all these low-dose schedules have a favorable safety profile and may provide an adequate tumor control in patients with metastatic breast cancer. However, there are no data in literature reporting the patient’s tolerance and response to subsequent lines of chemotherapy after receiving metronomic regimens. Methods: We retrospectively analyzed 40 patients with metastatic breast cancer treated with low doses of Cyclophosphamide and/or Methotrexate and/or Capecitabine in a single center from June 2009 to April 2014. The following data were collected: age, hormone and epidermal growth factor receptor 2 (HER-2) status, number of lines of chemotherapy prior to and after low-dose metronomic treatment, duration of metronomic treatment, toxicity reason for treatment discontinuation. Duration of low-dose metronomic chemotherapy was also correlated with the variables analyzed and treatment outcomes. Results: The median time on metronomic chemotherapy was 5.4 months. The most frequent drugs administered were cyclophosphamide, methotrexate and capecitabine alone. Asthenia, myelotoxicity, gastrintestinal symptoms and handfoot syndrome were the most commonly recorded treatment related toxicity. Twenty six (65%) patients had the opportunity to receive a classic chemotherapy regimen following metronomic regimen interruption. Although patients who developed toxicity to low-dose metronomic chemotherapy remained less time (<6 months) in subsequent chemotherapy, there was no statistically significant difference among those who received more lines of chemotherapy. Discussion: This is the first report in the literature describing the efficacy of low-dose metronomic regimens and the tolerance to subsequent lines of treatments following a period of metronomic chemotherapy. Most of our patients were able to tolerate conventional chemotherapy regimens administered in full doses. Several patients received as many as three lines of additional chemotherapy for periods that exceeded 6 months of treatment, which suggests that the use of prolonged metronomic treatment does not affect a patient’s ability to tolerate subsequent therapy.

A Commentary: Herbal Medicine Offers Great Potential in Support of Metronomic Cancer Therapy

Background: In spite of the advances in Cancer treatment, limitations exist. Refractory cases and late presentations are particularly worrying. The uncertainty of cure and the high costs have led to the popularly of complementary and alternative medicine in cancer treatment. Herbal medicine has particular attraction because it has been shown to be working on a multi-targets direction: promoting apoptosis of cancer cells, anti-angiogenesis and immunomodulating. Research on creating a simple herbal formula with multiple effects of cancer control has started and showed in laboratory platforms promising results. Metronomic Chemotherapy: Attention on the use of old oral cytotoxic drugs in small doses for refractory and late cancer cases has started more than a decade. Satisfactory and good results have been found to be related to anti-angiogenesis, immunomodulations and cancer cell apoptosis. These findings are comparable to the use of multiple targets herbal medicine. Conclusion: Assumption is made that metronomic chemotherapy, combined with herbal medicine could be achieving synergistic effects and would be affordable to all patients.

Novel Approach to Chemotherapy and Administration Selection with Metronomic/Fractionated Dosing

Metronomic dosing of chemotherapy was introduced in the early 2000s and has since gained recognition as a potential game changer in the manner of which chemotherapy can be administered. There are several known candidates for metronomic dosing of chemotherapy with the potential for many more to be elucidated in the future. Minimized overall side effects, longer durations of treatment, potential minimization of multidrug resistance (MDR) mutations, potential less refractory responses, and the potential to safely use more than one chemotherapy treatments also make metronomic dosing of chemotherapy attractive. Metronomic dosing reduces common side effects and has the potential to reduce neutropenia, lymphocytopenia, and cognitive changes associated with maximum tolerated dosages (MTD). Methods of enhancing chemotherapy including fasting and administration of insulin are also discussed. Metronomic dosing combined with a patient’s molecular profile derived from biomarkers is particularly exciting. It holds significant potential with regard to administrating the most relevant chemotherapies and offers maximal beneficial results.

Gene Expression Changes in Colorectal Cancer during Metronomic Chemotherapy and High-Concentration Drug Administration

5-fluorouracil (5-FU) and oxaliplatin, either alone or in combination, are widely used in chemotherapy for advanced colorectal cancer. Among chemotherapeutic strategies, metronomic chemotherapy has recently demonstrated promising efficacy against otherwise chemoresistant neoplasms. However, data on the efficacy of metronomic applications in cancer stem cells are lacking. This cell population is characterized by resistance to most chemotherapeutic models. In this study, we investigated the efficacy of metronomic chemotherapy and compared it with high-concentration administration of 5-FU and oxaliplatin and their combination in colon adenocarcinoma cells and colon cancer stem cells. We assessed changes in expression levels of specific genes involved in 5-FU and oxaliplatin resistance (thymidylate synthase, DNA (cytosine-5)-methyltransferase 1, dihydrofolate reductase, serine hydroxymethyltransferase, DNA excision repair protein, dihydropyrimidine dehydrogenase) in relation to drug administration schedule using quantitative real-time polymerase chain reaction. We also examined changes in cell viability. Metronomic chemotherapy showed greater efficacy in gene expression levels in colorectal cancer cells, while high, single-concentration administration was more effective in colon cancer stem cells. Regarding cell viability, no significant change was observed between metronomic and single-dose treatments. These results suggest that metronomic chemotherapy may be more effective than high-dose chemotherapy in some patients with colorectal cancer, though high, single-concentration administration may be more effective against cancer stem cells.

Efficacy Study of Metronomic Chemotherapy in Metastatic Triple Negative Breast Cancer and Correlation with VEGF, TSP Levels

Background: Treatment refractory metastatic breast cancer patients are at best treated palliatively. We evaluated the effects of metronomic chemotherapy on survival outcomes in this population. Methods: Twenty eight subjects with treatment refractory (n = 21) and treatment naive (n = 7) MBC were included in an open label single arm efficacy study of metronomic chemotherapy. Patients were given a chemotherapy regimen of Tab. Cyclophosphamide 50 mg once daily and Tab. Methotrexate 2.5 mg twice in a week over a minimum period of 3 months or until the progression of their disease whichever was earlier. Monitoring of serum VEGF and Thrombospondin levels were done to correlate the response rates. Data were analysed using chi square test for proportions and Kaplan Meir Survival analysis. Results: The mean age of the study population was 51.5 ± 14.2 years. The mean duration of metronomic chemotherapy was 123.89 ± 97.6 days. Overall 71.4% had progressive disease and 28.6% had stable disease. 55.6% with treatment naive metastatic breast cancer had stable disease compared to 15.8% of treatment refractory metastatic breast cancer. There was also a significant improvement in progression free survival in those with tumor load less than 5 cms compared to >5 cms and in grade 2 compared to grade 3 disease. There was no correlation of serum VEGF levels before and after chemotherapy. There is no significant decrease in TSP levels. Conclusion: The results suggest stable response in one third of study patients. Performance status and tumor load are important predictors in this category of population. There is no significant correlation of serum VEGF and TSP levels before and after chemotherapy. Also, there was no significant correlation of biomarker levels in responding and non-responding patients.

Efficacy and Toxicity of Metronomic Capecitabine in Advanced Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is a hypervascular tumor. Metronomic chemotherapy;the continuous administration of low-dose chemotherapy;has both cytotoxic and antiangiogenic effects with low toxicity profile. We evaluated the efficacy and toxicity of metronomic capecitabine (MC) in patients with advanced HCC. Patients and Methods: From May 2010, we enrolled pts with either metastatic or locally advanced diseases not candidate for ablative or locoregional treatment and have acceptable liver function. Patients received oral MC in dose of 1000 mg/m2 daily in a 21 days cycle without interruption till disease progression or toxicity. Results: The study cohort consisted of 22 patients with a median age of 63 years. The median number of cycles received was 3 cycles (range 1 - 9). From 19 patients were evaluable for response we had 3 partial responders, 10 stable diseases and disease progression in 6 patients. Median time to progression (TTP) was 2.2 months (95% CI 1.4 - 6.24) and median survival time (OS) was 4.8 months (95% CI 1.8 - 7.9). For 20 patients evaluable for safety: no grade III/IV hematological toxic effects were observed. Non-hematological toxic effects included grade III vomiting and diarrhea in one patient and grade III hand-foot syndrome in one patient. There was no treatment-related mortality. Conclusions: Based on the observed response rate, TTP and OS;MC has a modest antitumor efficacy in pts with advanced HCC. However, due to its low toxicity profile it deserves further attention as a convenient, outpatient-based chemotherapy regimen.

Treatment-Induced Acute Leukaemia after Major Response to Cyclophosphamide-Based Metronomic Chemotherapy in Refractory Heavily Pre-Treated Prostate Cancer

Background: metronomic chemotherapy is based on antiangiogenic and immunologic mechanisms obtained by the administration of traditional cytotoxic drugs at lower concentration without rest periods. The low dosage induces fewer or no side effect compared to classic maximum tolerated dose administration (MTD). At present, no treatment related acute leukaemia was reported in cyclophosphamide-based metronomic chemotherapy (CMC). Case: We report the case of an 81-year-old man considered as having castration and chemo-refractory metastatic prostate cancer. CMC was started. Objective response was observed in this heavily pre-treated patient with progression free survival lasting more than 30 months. No toxicity was observed in this period and his autonomy was maintained. Finally, our patient developed a chemotherapy-induced acute myeloid leukaemia at 36th month of CMC. Conclusion: Even CMC is a well-tolerated treatment;secondary acute leukaemia is related to cumulative dose of cyclophosphamide. The benefit and the risk of long-term exposure to cyclophosphamide should be carefully balanced.

Sustained complete response of advanced hepatocellular carcinoma with metronomic capecitabine: a report of three cases

Background:Hepatocellular carcinoma(HCC)is one of the most frequent causes of cancer-related death.Sorafenib,a multitarget angiogenesis inhibitor,is an approved frontline treatment for advanced HCC in Western countries,although a complete response(CR)to treatment is infrequently reported.Capecitabine,an oral fluoropyrimidine,has been shown to be effect in both treatment-naïve patients and those previously treated with sorafenib.To date,how-ever,only one case of sustained CR to metronomic capecitabine has been reported.Case presentation:We describe three cases of advanced HCC treated with metronomic capecitabine where a CR was obtained.In the first case,capecitabine was administered as first line therapy;in the second case,capecitabine was used after intolerance to sorafenib;while in the third case,capecitabine was administered after sorafenib failure.Conclusion:Capecitabine is a potentially important treatment option for patients with advanced HCC and may even represent a cure in certain cases.

Metronomic chemotherapy of cyclophosphamide plus methotrexate for advanced breast cancer:Real-world data analyses and experience of one center

Background:Real-world data of the CM regimen[cyclophosphamide(CTX)plus methotrexate(MTX)]in metronomic pattern for advanced breast cancer is limited to small-sample or retrospective studies.This study was aimed to determine the effectiveness and safety of CM regimen in treating advanced breast cancer and to identify which patients are most likely to benefit from metronomic CM regimen.Methods:Patients with advanced breast cancer who received the metronomic CM regimen at least once between January 2009 and February 2019 in Sun Yat-sen University Cancer Center were included.Clinicopathological characteristics were collected.Overall survival(OS)and progression-free survival(PFS)were assessed using Kaplan-Meier estimates.Characteristics between patients with PFS<6 months and≥6 months were compared using the Chi-square test.Univariate and multivariate Cox regression model was used to estimate the prognostic factors for PFS and OS.Results:A total of 186 patients were included.The median age and follow-up were 49 years and 13.3 months,respectively.Over 50%of the patients were estrogen receptor/progesterone receptor-positive,and 60.8%had been heavily treated(≥3 lines).The objective response rate was 3.8%,the disease control rate at 12 weeks was 41.4%,and the clinical benefit rate at 24 weeks was 31.2%(58/186).The median PFS was 4.0 months[95%confidence interval(CI):3.6-4.7 months],the median duration of clinical benefit was 9.5 months(95%CI:8.2-10.8 months),and the median OS was 26.8 months(95%CI:20.9-37.7 months).Multivariate analysis for PFS revealed the CM regimen as maintenance therapy and no liver metastasis as favorable prognostic factors.Furthermore,patients without liver metastasis were more likely to have a PFS over 6 months than those with liver involvement(P=0.022).Liver,lymph node,and brain metastases were unfavorable prognostic factors for OS.The CM regimen was well-tolerated without newly reported adverse events.Conclusions:The CM regimen was effective in selected patients.In clinical practice,it would be better used as maintenance therapy and in patients without liver metastasis.Further follow-up investigation should be performed to examine its effect when used in combination with other treatments and determine predictive biomarkers.

COMBINED EFFECTS OF METRONOMIC ZOLEDRONATE WITH CORIOLUS VERSICOLOR IN A METASTATIC BREAST TUMOR MOUSE MODEL

Incidence of breast cancer is high in women worldwide and mortality usually results from tumor metastasis.Adjuvant chemotherapeutic,such as zoledronate(ZOL),has been used in metastatic breast cancer mainly for skeletal protection.Our previous studies demonstrated that Coriolus versicolor(CV)aqueous extract exhibited anti-tumor

Potential of mRNA vaccines to become versatile cancer vaccines

For centuries,therapeutic cancer vaccines have been developed and tried clinically.Way back in the late 19th century,the Father of Immunotherapy,William Coley had discovered that bacterial toxins were effective for inoperable sarcomas.In the 1970s,the Bacillus Calmette-Guérin(BCG)vaccine was repurposed,e.g.,for advanced melanomas.Then,therapeutic cancer vaccines based on tumorassociated antigens(found on the surfaces of cancer cells)were tried clinically but apparently have not made a really significant clinical impact.For repurposed pathogen vaccines,only the BCG vaccine was approved in 1989 for local application to treat nonmuscle-invading bladder cancers.Although the mildly toxic vaccine adjuvants deliberately added to conventional pathogen vaccines are appropriate for seasonal applications,when repurposed for continual oncology usage,toxicity may be problematic.In 2010,even with the approval of sipuleucel-T as the very first cancer vaccine(dendritic cell)developed for designated prostate cancers,it has also not made a really significant clinical impact.Perhaps more"user friendly"cancer vaccines should be explored.As from approximately 30 years ago,the safety and effectiveness of mRNA vaccination for oncology had already been studied,the current coronavirus disease 2019 pandemic,though disastrous,has given such progressively advancing technology a kickstart.For oncology,other virtues of mRNA vaccines seem advantageous,e.g.,rapid and versatile development,convenient modular design,and entirely cell-free synthesis,are being progressively recognized.Moreover,mRNAs encoding various oncology antigens for vaccination may also be tested with the combination of relatively non-toxic modalities of oncology treatments,e.g.,metformin or metronomic(low-dose,prolonged administration)chemotherapy.Admittedly,robust clinical data obtained through good quality clinical trials are mandatory.

Breast cancer:Muscarinic receptors as new targets for tumor therapy

The development of breast cancer is a complex process that involves the participation of different factors.Several authors have demonstrated the overexpression of muscarinic acetylcholine receptors(mAChRs)in different tumor tissues and their role in the modulation of tumor biology,positioning them as therapeutic targets in cancer.The conventional treatment for breast cancer involves surgery,radiotherapy,and/or chemotherapy.The latter presents disadvantages such as limited specificity,the appearance of resistance to treatment and other side effects.To prevent these side effects,several schedules of drug administration,like metronomic therapy,have been developed.Metronomic therapy is a type of chemotherapy in which one or more drugs are administered at low concentrations repetitively.Recently,two chemotherapeutic agents usually used to treat breast cancer have been considered able to activate mAChRs.The combination of low concentrations of these chemotherapeutic agents with muscarinic agonists could be a useful option to be applied in breast cancer treatment,since this combination not only reduces tumor cell survival without affecting normal cells,but also decreases pathological neo-angiogenesis,the expression of drug extrusion proteins and the cancer stem cell fraction.In this review,we focus on the previous evidences that have positioned mAChRs as relevant therapeutic targets in breast cancer and analyze the effects of administering muscarinic agonists in combination with conventional chemotherapeutic agents in a metronomic schedule.

Extended Daily Schedule of Temozolomide in Recurrent Glioblastoma: Single-Institution Report on a Series of 43 Patients

Background: Despite advances in surgical and first-line adjuvant treatment, glioblastoma multiforme (GBM) always recurs as disease natural history. Currently, there is no consensus as to the optimal second-line treatment of recurrent GBM. Patients and Methods: This is a retrospective study of a series of adult patients consecutively treated at a single institution for supratentorial cerebral GBM at first relapse. All patients had previously received the standard concomitant radiochemotherapy protocol as first-line therapy. At recurrence/progression, all patients were treated with a metronomic temozolomide (TMZ) schedule at a daily dosage of 50 mg/m2 of body surface. Radiologic, clinical, and laboratory data were collected for all patients, with a minimum follow-up of 18 months. Results: From January 2010 to June 2011, 43 patients were treated at our facility. A mean of 10 metronomic TMZ cycles (range, 3 - 21) was administered. Radiologically, we observed 2 complete responses (4.6%), 16 partial responses (37.2%), 18 stable disease (41.9%) and 7 progressive disease (16.3%). Steroids administration was safely tapered in 23 patients (53.5%). Karnofsky-Performance-Status (KPS) results improved in 20 patients (46.5%), stabilized in 20 (46.5%), and worsened in 3 patients (7.0%), with a mean KPS score increased from 65.1 at baseline to 75.3 at follow-up. Six-month progression-free survival was 53.5. One year after recurrence/progression diagnosis, 22 patients were still alive, with a 1-year overall survival rate of 51.6%. Conclusions: The proposed TMZ schedule seems a safe and effective option for patients with recurrent GBM, with high radiologic response rates and good clinical impact. Strict clinical observation of patients may enable obtaining better results than those already present in the literature and further investigation appears auspicable.

METRONOME Kalista CD转盘

METRONOME(文豪)是一家专注于数码产品生产的厂家。以法国的Toulouse为基地。该公司由一班数码科技专家组成。早期专为其它高级器材制造商作幕后设计及生产。而从1997年开始，这些数码专家决定以自己的牌子METRONOME闯天下，在短短三年内他们的数码产品就在欧洲各国及美国等地获得了极高的评价。目前METRONOME的产品分为合并式CD机、CD转盘和DIA转换解码器等三大类，Kal1sta是其中的旗舰级转盘，

现代趋势下电子鼓和贝斯如何影响爵士乐的律动

随着音乐技术的发展,爵士乐的节奏逐渐受到现代乐器的影响,尤其是低音吉他和程序鼓。研究表明,爵士乐的风格正在发生变化,从20世纪20年代初的传统爵士乐,到中期的bebop和灵魂爵士乐,再到后期的nu-jazz和funky jazz。这些变化主要是由于乐器的变化和制作技术的进步。本文旨在确定现代乐器如何影响爵士乐的节奏。通常,节奏被解释为一种独特的、有规律的、吸引人的方式,以维持一种不规则但有序的感觉,在这种情况下,节奏往往被定义为韵律,因为韵律有助于节奏的形成。