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Orlandi, Armando, Elena Iattoni, Carmela Di Dio, and Maria Alessandra Calegari. "Efficacia duratura e ottima tollerabilità di lapatinib associato a capecitabina metronomica in due pazienti con carcinoma mammario HER2-positivo." AboutOpen 3, no. 1 (December 29, 2017): 112–16. http://dx.doi.org/10.19156/abtpn.2017.0026.
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L’utilizzo di lapatinib in combinazione con capecitabina è associato in alcune pazienti a tossicità gastrointestinale e cutanea, che ne compromette la regolare assunzione limitando l’utilizzo di un’efficace schedula terapeutica nel carcinoma metastatico della mammella HER2-positivo, refrattario al trattamento con trastuzumab. I due casi clinici presentati mostrano il buon profilo di tossicità e l’efficacia della combinazione lapatinib (1250 mg/die) + capecitabina metronomica (500 mg 3 volte/die) (Oncology).
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Arvat, Emanuela. "Impiego della chemioterapia metronomica in pazienti con carcinoma surrenalico metastatico sottoposti a multipli trattamenti precedenti." L'Endocrinologo 15, no. 5 (September 25, 2014): 240. http://dx.doi.org/10.1007/s40619-014-0074-1.
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Revon-Rivière, Gabriel, Shripad Banavali, Laila Heississen, Wendy Gomez Garcia, Babak Abdolkarimi, Manickavallie Vaithilingum, Chi-Kong Li, et al. "Metronomic Chemotherapy for Children in Low- and Middle-Income Countries: Survey of Current Practices and Opinions of Pediatric Oncologists." Journal of Global Oncology, no. 5 (December 2019): 1–8. http://dx.doi.org/10.1200/jgo.18.00244.
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PURPOSE Low- and middle-income countries (LMICs) experience the burden of 80% of new childhood cancer cases worldwide, with cure rates as low as 10% in some countries. Metronomics combines frequent administrations of low-dose chemotherapy with drug repurposing, which consists of using already-approved drugs for new medical applications. With wide availability, limited costs, and little infrastructure needs, metronomics can be part of constraint-adapted regimens in these resource-limited settings—with the understanding that metronomics shall not be a substitute for standard treatments when available and doable. Our study aims to describe the experience, practices, opinions, and needs in metronomics of physicians working in LMICs. METHODS An online questionnaire was sent to more than 1,200 physicians in pediatric oncology networks in LMICs. Items included the type of center, physician’s demographics, experience in pediatric oncology, and experience with current knowledge of metronomics. Opinions and perspectives were explored using multiple-answer and open questions. RESULTS Of physicians, 17% responded. Of respondents, 54.9% declared that they had already used a metronomic regimen. The most frequently cited repositioned drugs were celecoxib (44%) followed by propranolol and valproic acid (17%). Respondents highlighted the advantages of outpatient use (20%) and expected low toxicity (24%). In considering the drawbacks of metronomics, 47% of responses highlighted the lack of scientific evidence or guidelines, 33% the availability or affordability of drugs, and 18% the problem of acceptance or compliance. Of physicians, 79% believed that use of metronomics will spread in LMICs in the near future and 98% of them were willing to participate in international metronomic protocols or registries. CONCLUSION Metronomics is already used in LMICs and is a potential answer to unmet needs in pediatric oncology. There is room for improvement in the availability of drugs and a necessity to develop collaborative protocols and research to generate level A evidence.
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Svoboda, Tomáš. "Metronomic chemotherapy in breast cancer." Onkologie 10, no. 4 (August 1, 2016): 161–65. http://dx.doi.org/10.36290/xon.2016.035.
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Teixeira, N. C. T., A. P. C. V. Bicalho, A. V. Vasconcelos, R. S. Horta, R. M. C. Cunha, and G. E. Lavalle. "Ciclooxygenase inhibitor and metronomic chemotherapy association for the treatment of metastatic anal sac carcinoma in dog: case report." Arquivo Brasileiro de Medicina Veterinária e Zootecnia 68, no. 4 (August 2016): 913–18. http://dx.doi.org/10.1590/1678-4162-8439.
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ABSTRACT Metronomic chemotherapy consists of an anticancer modality treatment. It is applicable in patients at an advanced stage, with the objective of increasing overall survival. The aim of this study was to report an anal sac apocrine carcinoma case in a dog with lymph node metastasis treated with metronomic chemotherapy sequential to surgery and conventional chemotherapy using gemcitabine and carboplatin. Metronomic chemotherapy was associated with cyclooxygenase-2 (COX-2) inhibitors, due to strong tumor COX-2 immunohistochemistry expression. Metronomic chemotherapy was initiated with cyclophosphamide, but it was replaced by lomustine, also in metronomic dosage, due to adverse effects. Treatment showed effectiveness, since the patient's overall survival exceeded 1095 days (36 months), considerably higher than the mean overall survival expected for this pathology.
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Olovnikov, Alexey M. "Planetary Metronome as a Regulator of Lifespan and Aging Rate: The Metronomic Hypothesis." Biochemistry (Moscow) 87, no. 12-13 (December 2022): 1640–50. http://dx.doi.org/10.1134/s0006297922120197.
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Abstract A metronomic mechanism for the duration control of ontogenetic cycle periods of an animal is proposed. The components of the proposed metronomic system include the ventricular system of the brain, planet Earth as a generator of metronomic signals, and temporal DNA (tDNA) as a substrate that is epigenetically marked to measure elapsed time of ontogenesis. The metronomic system generates repetitive signals in the form of hydrodynamic disturbances in the cerebrospinal fluid (CSF). The metronomic effect arises due to the superposition of two processes – the near-wall unidirectional flow of CSF and oscillations in the movement of the planet. Hydrodynamic impacts of the metronome are transformed into nerve impulses that initiate epigenetic modification of tDNA in neurons, changing the content of factors expressed by this DNA for innervated targets of the body. The duration of ontogenetic cycle periods, including duration of the adult life, depends on the rate of addition of epigenetic marks to tDNA. This rate depends mainly on the frequency of the metronomic signals used by each particular species. But epigenetic modifications can also be influenced by factors that modulate metabolism and the rate of chromatin modifications, such as a calorie-restricted diet.
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Su, Nai-Wen, and Yu-Jen Chen. "Metronomic Therapy in Oral Squamous Cell Carcinoma." Journal of Clinical Medicine 10, no. 13 (June 26, 2021): 2818. http://dx.doi.org/10.3390/jcm10132818.
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Metronomic therapy is characterized by drug administration in a low-dose, repeated, and regular manner without prolonged drug-free interval. The two main anticancer mechanisms of metronomic therapy are antiangiogenesis and immunomodulation, which have been demonstrated in several delicate in vitro and in vivo experiments. In contrast to the traditional maximum tolerated dose (MTD) dosing of chemotherapy, metronomic therapy possesses comparative efficacy but greatlydecreases the incidence and severity of treatment side-effects. Clinical trials of metronomic anticancer treatment have revealed promising results in a variety cancer types and specific patient populations such as the elderly and pediatric malignancies. Oral cavity squamous cell carcinoma (OCSCC) is an important health issue in many areas around the world. Long-term survival is about 50% in locally advanced disease despite having high-intensity treatment combined surgery, radiotherapy, and chemotherapy. In this article, we review and summarize the essence of metronomic therapy and focus on its applications in OCSCC treatment.
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Zhang, Mu, Chen Chen, Feng Su, Zhiguo Huang, Xiangmin Li, and Xiaogang Li. "Knockdown of Hypoxia-Inducible Factor 1α Improved the Efficacy of Low-Dose Metronomic Chemotherapy of Paclitaxel in Human Colon Cancer Xenografts." Technology in Cancer Research & Treatment 16, no. 5 (August 29, 2016): 609–19. http://dx.doi.org/10.1177/1533034616665720.
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Low-dose metronomic chemotherapy represents a new strategy for solid tumor treatments with a strong antiangiogenic activity and few side effects. However, low-dose metronomic therapy alone is not always as effective as traditional chemotherapy on eradication of tumor. On the contrary, low-dose metronomic in some cases could stimulate tumor growth due to hypoxia of tumor cells induced during therapy. Our study aimed to investigate whether knockdown of hypoxia-inducible factor-1α expression in tumor cell could facilitate low-dose metronomic therapy with paclitaxel for human colon cancer. Human colon cancer cell line (HT-29) stably transfected with specific short hairpin RNAs silencing hypoxia-inducible factor-1α exhibited marked attenuation of hypoxia-induced expression of the target genes such as vascular endothelial growth factor, glucose transporter 1, and P-glycoprotein. Compared with HT-29-c xenograft tumor model established by subcutaneous injection of HT-29 cells stably transfected with scrambled control short hairpin RNA, HT-29-ih xenograft tumor model showed more significant and long-lasting antitumor responses of empirical metronomic paclitaxel regimens, accompanied by drastic angiogenesis decrease and neglectable toxicity. All these data indicated that the combination of paclitaxel low-dose metronomic therapy with hypoxia-inducible factor-1α knockdown might provide a potent battle against colon cancer.
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Cazzaniga, Marina Elena, Nicoletta Cordani, Serena Capici, Viola Cogliati, Francesca Riva, and Maria Grazia Cerrito. "Metronomic Chemotherapy." Cancers 13, no. 9 (May 6, 2021): 2236. http://dx.doi.org/10.3390/cancers13092236.
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Metronomic chemotherapy treatment (mCHT) refers to the chronic administration of low doses chemotherapy that can sustain prolonged, and active plasma levels of drugs, producing favorable tolerability and it is a new promising therapeutic approach in solid and in hematologic tumors. mCHT has not only a direct effect on tumor cells, but also an action on cell microenvironment, by inhibiting tumor angiogenesis, or promoting immune response and for these reasons can be considered a multi-target therapy itself. Here we review the state of the art of mCHT use in some classical tumour types, such as breast and no small cell lung cancer (NSCLC), see what is new regarding most recent data in different cancer types, such as glioblastoma (GBL) and acute myeloid leukemia (AML), and new drugs with potential metronomic administration. Finally, a look at the strategic use of mCHT in the context of health emergencies, or in low –and middle-income countries (LMICs), where access to adequate healthcare is often not easy, is mandatory, as we always need to bear in in mind that equity in care must be a compulsory part of our medical work and research.
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Mutsaers, Anthony J. "Metronomic Chemotherapy." Topics in Companion Animal Medicine 24, no. 3 (August 2009): 137–43. http://dx.doi.org/10.1053/j.tcam.2009.03.004.
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Kamen, Barton A. "Metronomic Therapy." Journal of Pediatric Hematology/Oncology 27, no. 11 (November 2005): 571–72. http://dx.doi.org/10.1097/01.mph.0000192148.90120.15.
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Maiti, Rituparna. "Metronomic chemotherapy." Journal of Pharmacology and Pharmacotherapeutics 5, no. 3 (2014): 186. http://dx.doi.org/10.4103/0976-500x.136098.
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Sun, Xiaofei, Zijun Zhen, Ying Guo, Yuanhong Gao, Juan Wang, Yu Zhang, Jia Zhu, et al. "Oral Metronomic Maintenance Therapy Can Improve Survival in High-Risk Neuroblastoma Patients Not Treated with ASCT or Anti-GD2 Antibodies." Cancers 13, no. 14 (July 13, 2021): 3494. http://dx.doi.org/10.3390/cancers13143494.
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Despite aggressive treatment, the prognosis of high-risk NB patients is still poor. This retrospective study investigated the benefits of metronomic maintenance treatment (MT) in high-risk NB patients without ASCT or GD2 antibody therapy. Patients aged ≤ 21 years with newly diagnosed high-risk NB were included. Patients with complete/very good partial remission (CR/VGPR/PR) to conventional treatment received, or not, oral metronomic MT for 1 year. Two hundred and seventeen high-risk NB patients were enrolled. One hundred and eighty-five (85%) had a CR/VGPR/PR to conventional treatment, of the patients with stage 4, 106 receiving and 61 not receiving oral metronomic MT, and the 3-year event-free survival (EFS) rate was 42.5 ± 5.1% and 29.6 ± 6%, respectively (p = 0.017), and overall survival (OS) rate was 71.1 ± 4.7% and 59.4 ± 6.4%, respectively (p = 0.022). A total of 117 high-risk patients with oral metronomic MT had EFS rate of 42.7 ± 4.8%. The toxicity of MT was mild. For high-risk NB patients without ASCT or anti-GD2 antibody therapy, stage 4, MYCN amplication and patients with stage 4 not receiving oral metronomic MT after CR/VGPR/PR were independent adverse prognostic factors. Oral metronomic MT can improve survival in high-risk NB patients in CR/VGPR/PR without ASCT or anti-GD2 antibodies therapy.
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Patwardhan, A. R., J. M. Evans, E. N. Bruce, D. L. Eckberg, and C. F. Knapp. "Voluntary control of breathing does not alter vagal modulation of heart rate." Journal of Applied Physiology 78, no. 6 (June 1, 1995): 2087–94. http://dx.doi.org/10.1152/jappl.1995.78.6.2087.
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Variations in respiratory pattern influence the heart rate spectrum. It has been suggested, hence, that metronomic respiration should be used to correctly assess vagal modulation of heart rate by using spectral analysis. On the other hand, breathing to a metronome has been reported to increase heart rate spectral power in the high- or respiratory frequency region; this finding has led to the suggestion that metronomic respiration enhances vagal tone or alters vagal modulation of heart rate. To investigate whether metronomic breathing complicates the interpretation of heart rate spectra by altering vagal modulation, we recorded the electrocardiogram and respiration from eight volunteers during three breathing trials of 10 min each: 1) spontaneous breathing (mean rate of 14.4 breaths/min); 2) breathing to a metronome at the rate of 15, 18, and 21 breaths/min for 2, 6, and 2 min, respectively; and 3) breathing to a metronome at the rate of 18 breaths/min for 10 min. Data were also collected from eight volunteers who breathed spontaneously for 20 min and breathed metronomically at each subject's mean spontaneous breathing frequency for 20 min. Results from the three 10-min breathing trials showed that heart rate power in the respiratory frequency region was smaller during metronomic breathing than during spontaneous breathing. This decrease could be explained fully by the higher breathing frequencies used during trials 2 and 3 of metronomic breathing. When the subjects breathed metronomically at each subject's mean breathing frequency, the heart rate powers during metronomic breathing were similar to those during spontaneous breathing. Our results suggest that vagal modulation of heart rate is not altered and vagal tone is not enhanced during metronomic breathing.
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Phillips, Cameron, Giulio Francia, Robert S. Kerbel, and Urban Emmenegger. "Personalized use of metronomic cyclophosphamide for DNA repair deficient castration-resistant prostate cancer: A phase II trial." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): TPS346. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.tps346.
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TPS346 Background: There is a continued need to identify novel targets for the treatment of metastatic, castration-resistant prostate cancer (mCRPC). DNA damage repair (DDR) aberrations are emerging as such a target: 20%-30% of mCRPCs harbor DDR gene aberrations, rendering tumors particularly sensitive to DNA damaging agents and poly ADP-ribose polymerase inhibitor (PARPi) therapy. 88% of men with DDR deficient mCRPC responded to the PARPi olaparib in a phase II trial, whereas in unselected mCRPC patients the metronomic use of the DNA damaging agent cyclophosphamide (CPA) resulted in response rates of 25-60%. Intriguingly, in randomized phase II trials of unselected ovarian and triple-negative breast cancer (ie tumor types enriched for DDR defects), metronomic CPA alone was as active as metronomic CPA plus the PARPi veliparib. Based on this we hypothesize that DDR deficient mCRPC is particularly sensitive to metronomic CPA. To the best of our knowledge this is the first attempt to utilize metronomic CPA in a personalized manner. Our study has the potential to define metronomic CPA as an affordable and well-tolerated alternative to PARPi therapy in men with DDR deficient mCRPC. Methods: To study if metronomic CPA achieves a similar response rate (ie ≥85%) in DDR deficient mCRPC as seen with olaparib, men with mCRPC progressing after 1-2 lines of systemic therapy will undergo circulating tumor DNA based testing for BRCA1/2 or ATM aberrations. Patients with such aberrations will proceed with metronomic CPA (50 mg po daily). Primary endpoint: RECIST 1.1 and/or ≥50% PSA response rate at 12 weeks. Secondary endpoints include biochemical, radiological and clinical progression-free survival. Applying the Optimal Simon's Two-Stage design, and using a type I error rate of 0.05 and a power of 0.8, in the first stage we plan to enroll 14 patients. If there are ≤10 or fewer responses, the study will be stopped. Otherwise, another 19 patients will be accrued as part of the second stage.
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Sul, J., K. S. Panageas, A. B. Lassman, A. Hormigo, C. Nolan, I. T. Gavrilovic, S. A. Grimm, L. M. DeAngelis, and L. E. Abrey. "A randomized phase II trial of concurrent temozolomide (TMZ) and radiotherapy (RT) followed by dose dense compared to metronomic TMZ and maintenance cis-retinoic acid for patients with newly diagnosed glioblastoma multiforme (GBM)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2031. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2031.
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2031 Background: Metronomic and dose dense scheduling are alternatives to conventional TMZ regimens to overcome drug resistance in part by depleting O-6 methylguanine-DNA methyltransferase (MGMT). Furthermore, metronomic TMZ may inhibit endothelial recovery and act as an anti-angiogenic therapy; dose dense TMZ increases the intensity of drug delivery. Objective: To determine the overall (OS) and progression free survival (PFS) of patients with newly diagnosed GBM treated with concurrent TMZ and RT followed by dose dense or metronomic TMZ and maintenance cis-retinoic acid. Methods: Patients with newly diagnosed, histologically confirmed GBM underwent standard RT with TMZ. Upon completion of this treatment, patients were randomized to receive dose-dense TMZ (150mg/m2, days 1–7 and 15–21 of a 28 day cycle) or metronomic TMZ (50mg/m2 daily in 28 day cycles), for 6 cycles. Maintenance cis-retinoic acid was prescribed following the 6 cycles of adjuvant TMZ. OS and PFS were calculated from date of diagnosis. Prospective correlative tissue analysis of MGMT status is planned. A Simon minimax 2-stage design was used for each cohort. If either group has 70% survival probability at 1 year, further evaluation in a phase III trial will be recommended. Results: 51 patients were randomized: 24 to metronomic, and 27 to dose dense. Median age is 57, and median KPS 90. 26 patients have progression of disease (POD), with a median follow up of 5 months. Grade 3/4 hematologic toxicity occurred in 7 patients (14%), 3 in the metronomic and 4 in the dose dense arm. Conclusions: Our patient population is comparable to that of other upfront GBM treatment trials. Metronomic and dose dense TMZ appear to be well tolerated with equivalent toxicities. Early analysis suggests that patients on the dose dense regimen may have better PFS than those on the metronomic arm. [Table: see text] No significant financial relationships to disclose.
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Vergnenegre, Alain, Isabelle Monnet, Acya Bizieux, Marie Bernardi, Anne Marie Chiapa, Hervé Léna, Christos Chouaïd, and Gilles Robinet. "Open-label Phase II trial to evaluate safety and efficacy of second-line metronomic oral vinorelbine–atezolizumab combination for stage-IV non-small-cell lung cancer – VinMetAtezo trial, (GFPC‡ 04-2017)." Future Oncology 16, no. 4 (February 2020): 5–10. http://dx.doi.org/10.2217/fon-2019-0730.
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Metronomic chemotherapy is defined as frequent low-dose administration without prolonged drug-free breaks. Combining immune-checkpoint inhibitors and metronomic chemotherapy is a new approach to improve responses and delay onset of resistance to immune-checkpoint inhibitors. This multicenter, Phase II, open-label, single-arm study was designed to assess the safety and efficacy of metronomic oral vinorelbine in combination with immune-checkpoint inhibitors in advanced non-small-cell lung cancers progressing after first-line platinum-based chemotherapy. The recommended metronomic oral vinorelbine dose will be determined during a safety run-in period including 12 patients; the main study will include 59 additional patients. The primary outcome is progression-free survival at 4 months. Secondary outcomes are safety of the combination, median overall survival, objective response rate, disease-control rate at 4 months and quality of life (NCT03801304).
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Ma, Fei, Xinlan Liu, Yanxia Shi, Xiuwen Guan, Huihui Li, Xiaojia Wang, Yuee Teng, et al. "Abstract P1-16-02: A randomized phase II study investigating oral metronomic vinorelbine versus conventional dosage of vinorelbine in HER2-negative metastatic breast cancer previously treated with anthracycline or taxane:clinical results and biomarker analysis." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–16–02—P1–16–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-16-02.
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Abstract Background: Metronomic chemotherapy, defined as frequent administration of. chemotherapeutic agents at a non-toxic dose without extended rest periods, can overcome drug resistance and achieve disease control with reduced toxicity compared to conventional chemotherapy in maximum tolerated dose by shifting the therapeutic target from tumor cells to tumor endothelial cells. Some of the previous studies of oral vinorelbine have shown good data in efficacy and safety in advanced breast cancer. Methods: The multicenter, open-label, non-inferiority, randomized phase 2 study (NCT03854617) aimed to evaluate the efficacy and safety of oral metronomic vinorelbine in 13 hospitals in China. Eligible HER2-negative breast cancer patients previously treated with anthracycline or taxane regimens were randomized (1:1) to receive metronomic dosage of oral vinorelbine (50mg/3 times a week) or conventional dosage of oral vinorelbine (60mg/m2 weekly for cycle 1 and 80mg/m2 weekly for subsequent cycles in the absence of grade 3 or 4 toxicity) for first-line/second-line chemotherapy. The primary end point was Disease Control Rate (DCR) and a non-inferiority margin of 6% was defined for DCR. Patient characteristics, progression-free survival (PFS), overall survival (OS) and safety/adverse events (AEs) were among the parameters assessed. The expression of 27 cytokines was profiled longitudinally in these patients at baseline and at regular intervals during therapy. Results: Between February 2019 and September 2020, a total of 171 patients were enrolled and randomized to metronomic dosage group (86 patients) and conventional dosage group (85 patients). 136 patients were hormone receptor(HR)positive and 117 patients (68.4%) had visceral metastases. The DCR was 59.3% (95% CI:48.17% to 69.78%) in the metronomic dosage group and 67.1% (95% CI:56.02% to 76.87%) in the conventional dosage group. Whereas, the 18-month survival rate was higher in the metronomic dosage group than that in the conventional dosage group (68.7% vs 43.0%).The median progression-free survival in the metronomic dosage group was 2.8 months (95% CI:1.40 to 3.50) compared with 4.1 months (95% CI:2.80 to 6.20) in the conventional dosage group. Grade 3 or higher adverse events were significantly less frequent in patients in the metronomic dosage group than patients in the conventional dosage group (19.8% vs 48.2%, P<0.001). By comparing the variation of cytokine profiles at baseline and after 6-week treatment in 122 patients, multilevel partial least squares discriminant analysis (PLS-DA) suggested the variation of VEGF, MIP-1α, IL-1B, IL-17, MCP-1, IL-13, PDGF-BB, IL-4 and RANTES were significantly different between the metronomic dosage group and the conventional dosage group during the treatment (all VIP values > 1.2). As for the patients in the metronomic dosage group, GM-CSF, MCP-1, TNF-α, IL-10, IL-13 and MIP-1α were potential biomarkers between the response patients and non-response patients (all VIP values > 1.2). Conclusions: Oral metronomic vinorelbine decreased the risk of severe toxicity significantly and may be an option for older patients and for those intolerable to standard chemotherapy with proper predictive biomarkers, though this study couldn’t prove to show the non-inferiority of oral metronomic vinorelbine for first-line or second-line chemotherapy previously treated with anthracycline or taxane in HER2-negative metastatic breast cancer. Citation Format: Fei Ma, Xinlan Liu, Yanxia Shi, Xiuwen Guan, Huihui Li, Xiaojia Wang, Yuee Teng, Qiang Liu, Jin Yang, Man Li, Qingyuan Zhang, Weihong Zhao, Caiwen Du, Lili Sheng, Binghe Xu. A randomized phase II study investigating oral metronomic vinorelbine versus conventional dosage of vinorelbine in HER2-negative metastatic breast cancer previously treated with anthracycline or taxane:clinical results and biomarker analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-02.
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Mutlu, H., H. Bozcuk, M. Ozdogan, M. Artac, H. S. Coskun, A. Kargi, M. Uysal, and B. Savas. "Impressive survival data with semimetronomic oral chemotherapy with old agents in heavily treated metastatic breast cancer patients." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 1082. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.1082.
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1082 Background: To assess the efficacy of semi-metronomic regimen metronomic cyclophosphomide with oral etoposide in heavily treated patients with metastatic breast cancer. Methods: Consecutive metastatic breast cancer (MBC) patients predominantly refractory to antracyclines, taxanes, and antimetabolites receiving semi-metronomic regimen of metronomic cyclophosphomide with oral etoposide were evaluated for clinical efficacy and toxicity. This novel regimen comprised of continuous oral cyclophosphomide 50 mg/day, and oral etoposide given as 2 x 50 mg/day for 5 days. Results: A total of 42 MBC patients received this treatment in 2.5 years (May 2005-October 2008). The median age was 51.5 (29–81), ER and/or PR receptor status was positive in 67%, and c-erb-B2 overexpression existed in 50%. The biologically favorable group, hormone responsive and c-erb-B2 negative comprised of 36% of cases. The portions of patients with visceral metastases, cranial metastases, and 2 or more organ involvement were 82%, 24%, and 65%, respectively. Subjects had received this treatment in the fourth or more advanced setting in 50% of cases (after a median of 2.5 cycles). The median overall and progression free survival figures were 25 and 10.5 months, respectively. No toxic mortality occurred, and the treatment was well tolerated. Toxicity and response data are being updated currently. Conclusions: Semi-metronomic treatment with metronomic cyclophosphomide and oral etoposide is a novel and effective strategy in heavily pretreated MBC patients. Survival data and low cost may make this regimen a highly preferable option in this difficult patient group. No significant financial relationships to disclose.
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Ma, Jun, Yu-Pei Chen, Ying Sun, Qin Zhou, Kun-Yu Yang, Feng Jin, Xiao-Dong Zhu, et al. "Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: A phase 3, multicenter, randomized controlled trial." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 6003. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.6003.
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6003 Background: Patients suffering from locoregionally advanced nasopharyngeal carcinoma (NPC) commonly develop disease recurrence, despite a high rate of complete clinical remission after standard of care (concurrent cisplatin-radiotherapy, with or without induction chemotherapy). The benefit of additional adjuvant chemotherapy remains unclear. Methods: Patients with high-risk locoregionally advanced NPC (stage III to IVA, excluding T3-4N0 and T3N1), and with no locoregional disease or distant metastasis after definitive chemoradiotherapy, were eligible. They were randomly assigned (1:1) within 12 to 16 weeks after the last radiation dose to receive either capecitabine at a dose of 650 mg/m2 twice daily for 1 year (metronomic capecitabine group) or observation (standard-therapy group). The primary end point was recurrence-free survival (RFS). The calculated sample size was 201 per group, with an 80% power (two-sided α 0.05) to detect a target hazard ratio (HR) of 0.52. Results: A total of 406 patients underwent randomization, comprising 204 in the metronomic capecitabine group and 202 in the standard-therapy group. After a median follow-up of 36 months (corresponding to 43 months when calculated from the start of standard therapy), the estimated 3-year RFS was 85.9% in the metronomic capecitabine group, as compared with 76.5% in the standard-therapy group (intention-to-treat population; HR 0.51, 95% confidence interval 0.32–0.81; P = 0.003). The incidence of grade 3 adverse events was 17.4% in the metronomic capecitabine group and 5.5% in the standard-therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (9.0%). One grade 4 neutropenia occurred in the metronomic capecitabine group. Neither group sufferd from treatment-related deaths. During treatment, there was no clinically meaningful deterioration of health-related quality of life associated with the use of metronomic adjuvant capecitabine. Conclusions: The addition of metronomic capecitabine as adjuvant therapy to chemoradiotherapy significantly improved RFS in locoregionally advanced NPC, with a manageable safety profile and no compromise to quality of life. Clinical trial information: NCT02958111. [Table: see text]
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Simsek, Cem, Ece Esin, and Suayib Yalcin. "Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience." Journal of Oncology 2019 (March 20, 2019): 1–31. http://dx.doi.org/10.1155/2019/5483791.
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Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts’ immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.
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Spiliopoulou, Pavlina, Samantha Hinsley, Iain A. McNeish, Patricia Roxburgh, and Ros Glasspool. "Metronomic oral cyclophosphamide in relapsed ovarian cancer." International Journal of Gynecologic Cancer 31, no. 7 (May 20, 2021): 1037–44. http://dx.doi.org/10.1136/ijgc-2021-002467.
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ObjectivesTo describe the clinical activity of metronomic cyclophosphamide in a population of patients with recurrent ovarian cancer, and to identify predictors of clinical response.MethodsWe retrospectively reviewed all patients treated at our institution with oral metronomic cyclophosphamide for relapsed ovarian cancer between January 2012 and December 2016. These were identified from electronic chemotherapy prescription records. The primary endpoint was response rate by combined Gynecologic Cancer InterGroup (GCIG) criteria. Data on patient demographics, previous therapies, platinum resistance, germline BRCA1/2 (gBRCA1/2) status, disease response by radiological or cancer antigen 125 (CA125) criteria alone, adverse events secondary to metronomic cyclophosphamide treatment, progression-free survival, and overall survival were also evaluated.Results50 out of 68 patients treated with oral metronomic cyclophosphamide were evaluable for disease response. By combination criteria (radiological plus CA125), complete response was 0%, partial response 32%, stable disease 16%, and progressive disease 52%. In the intention-to-treat population (n=68), progression-free survival and overall survival were 2.6 months and 6 months, respectively. Having a gBRCA1/2 mutation reduced the risk of disease progression by radiological criteria (OR 0.07, 95% CI 0.008 to 0.67, p=0.02), and patients with gBRCA1/2 mutations had improved progression-free survival (7.9 vs 2.5 months, HR 0.4, 95% CI 0.23 to 0.74, p=0.003) and overall survival (15.5 vs 6 months, HR 0.49, 95% CI 0.28 to 0.85, p=0.02) with metronomic cyclophosphamide when compared with patients without gBRCA1/2 mutations (or unknown gBRCA1/2 status).ConclusionOral metronomic cyclophosphamide showed a clinical benefit in 48% of patients with recurrent ovarian cancer. gBRCA1/2 status can be an independent predictor of response.
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Pietras, Kristian, and Douglas Hanahan. "A Multitargeted, Metronomic, and Maximum-Tolerated Dose “Chemo-Switch” Regimen is Antiangiogenic, Producing Objective Responses and Survival Benefit in a Mouse Model of Cancer." Journal of Clinical Oncology 23, no. 5 (February 10, 2005): 939–52. http://dx.doi.org/10.1200/jco.2005.07.093.
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Purpose A transgenic mouse model has revealed parameters of the angiogenic switch during multistep tumorigenesis of pancreatic islets, and demonstrated efficacy of antiangiogenic therapies. Pericytes have been revealed as functionally important for tumor neovasculature, using kinase inhibitors targeting their platelet-derived growth factor receptors (PDGFRs). Additionally, vascular endothelial growth factor receptor (VEGFR) inhibitors and metronomic chemotherapy show modest benefit against early- but not late-stage disease. Materials and Methods Seeking to improve efficacy against otherwise intractable end-stage pancreatic islet tumors, two receptor tyrosine kinase inhibitors, imatinib and SU11248, were used to disrupt PDGFR-mediated pericyte support of tumor endothelial cells in concert with maximum-tolerated dose (MTD) or metronomic chemotherapy and/or VEGFR inhibition. Results Imatinib, despite equivocal efficacy as monotherapy, reduced pericyte coverage of tumor vessels and enhanced efficacy in combination with metronomic chemotherapy or VEGFR inhibition. A regimen involving all three was even better. MTD using cyclophosphamide caused transitory regression, but then rapid regrowth, in contrast to metronomic cyclophosphamide plus imatinib, which produced stable disease. The MTD regimen elicited apoptosis of tumor cells but not endothelial cells, whereas the other regimens increased endothelial cell apoptosis concordant with efficacy. A “chemo-switch” protocol, involving sequential MTD and then metronomic chemotherapy, overlaid with multitargeted inhibition of PDGFR and VEGFR, gave complete responses and unprecedented survival advantage in this model. Conclusion This study demonstrates a potentially tractable clinical strategy in a stringent preclinical model, wherein standard-of-care chemotherapy is followed by a novel maintenance regimen: PDFGR is targeted to disrupt pericyte support, while metronomic chemotherapy and/or VEGFR inhibitors target consequently sensitized endothelial cells, collectively destabilizing pre-existing tumor vasculature and inhibiting ongoing angiogenesis.
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Trefzer, T., S. Stoelting, A. Lemke, J. Kisro, A. Steinke, S. O. Peters, and T. Wagner. "Different responses of circulating endothelial progenitor cells and VEGF-plasma concentrations to low-dose metronomic and conventional chemotherapy." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14053. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14053.
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14053 Background: Endothelial progenitor cells (EPCs) may participate in tumor angiogenesis by providing cellular supply. This is a study that compares the effects of two conventional combination chemotherapy schedules to low-dose metronomic trofosfamide (an oral derivate of cyclophosphamide), using the number of circulating EPCs and vascular endothelial growth factor (VEGF) plasma levels in cancer patients. Methods: We measured circulating EPC and VEGF levels in 24 patients that received conventional chemotherapy for either breast cancer in an adjuvant setting or malignant lymphoma, and in 18 patients receiving metronomic chemotherapy with or without celecoxib for advanced cancer. Blood samples were obtained three times: before starting chemotherapy, 10 and 21 days after starting chemotherapy. Peripheral blood EPC levels were determined by fluorescence flow cytometry and defined by CD34- and VEGF-R2-positivity. VEGF plasma concentration was determined by ELISA. Results: The number of circulating EPCs showed a two-fold increase 21 days after conventional chemotherapy but a significant decrease under metronomic chemotherapy. VEGF-plasma-concentrations remained stable in patients under metronomic chemotherapy but significantly increased under conventional chemotherapy.This increase in VEGF plasma levels occurred even in patients that received chemotherapy in an adjuvant setting in supposed absence of tumor. Conclusions: Low-dose metronomic trofosfamide significantly decreased circulating EPCs while conventional chemotherapy increased both the number of circulating EPC and VEGF-concentrations. The increase of VEGF even in an adjuvant setting of chemotherapy without the presence of a tumor may be caused by chemotherapy-induced endothelial cell destruction. Metronomic scheduling of certain cytotoxic drugs may thus prevent tumor progression by inhibiting both tumor cell proliferation and angiogenesis. No significant financial relationships to disclose.
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Ueno, Takayuki, Norikazu Masuda, Shunji Kamigaki, Takashi Morimoto, Shigehira Saji, Shigeru Imoto, Hironobu Sasano, and Masakazu Toi. "Differential Involvement of Autophagy and Apoptosis in Response to Chemoendocrine and Endocrine Therapy in Breast Cancer: JBCRG-07TR." International Journal of Molecular Sciences 20, no. 4 (February 24, 2019): 984. http://dx.doi.org/10.3390/ijms20040984.
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Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, we studied autophagy-related markers, beclin 1 and LC3, and apoptosis-related markers, TUNEL and M30, in pre- and post-treatment cancer tissues from a multicenter neoadjuvant trial, JBCRG-07, in which oral cyclophosphamide plus letrozole were administered to postmenopausal patients with HR-positive breast cancer. Changes in the levels of markers were compared with those following neoadjuvant endocrine therapy according to clinical response. Apoptosis, in addition to autophagy-related markers, increased following metronomic chemoendocrine therapy and such increases were associated with clinical response. By contrast, following endocrine therapy, the levels of apoptosis-related markers did not increase regardless of clinical response, whereas the levels of autophagy-related markers increased. Furthermore, levels of the apoptosis-related marker, M30, decreased in responders of endocrine therapy, suggesting that the induction of apoptosis by metronomic chemoendocrine therapy was involved in the improved clinical outcome compared with endocrine therapy. In conclusion, metronomic chemoendocrine therapy induced a different cellular reaction from that of endocrine therapy, including the induction of apoptosis, which is likely to contribute to improved efficacy compared with endocrine therapy alone.
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Marmorino, Federica, Chiara Cremolini, Fotios Loupakis, Lisa Salvatore, Marta Schirripa, Carlotta Antoniotti, Teresa Di Desidero, et al. "Metronomic capecitabine (cape) and cyclophosphamide (CTX) for refractory metastatic colorectal cancer (mCRC): Results of a phase II trial." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e14577-e14577. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e14577.
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e14577 Background: The protracted exposure to low doses of cytotoxics according to metronomic schedules reported encouraging results in the treatment of different malignancies. In a recent trial from our group, the association of a single standard dose of CTX followed by metronomic UFT and CTX with celecoxib showed a very favourable safety profile and promising activity in a cohort of heavily pre-treated patients (pts) with gastrointestinal tumors (Allegrini, 2012). The aim of the present trial was to prospectively evaluate the activity of metronomic cape and CTX in a population of refractory mCRC pts. Methods: Pts with documented diagnosis of CRC, progressed during or within 3 mos from the last administration of standard therapies, were eligible. They received cape 800 mg PO bid and CTX 50 mg PO once daily. Treatment was administered continuously until disease progression. Primary endpoint was 2 mos-progression free rate (2m-PFR). Hypothesizing a 2m-PFR of 10% for refractory mCRC pts with no therapeutic options, metronomic cape plus CTX would have been judged promising for an estimated increase from 10 to 35% in 2m-PFR. According to the Fleming single-stage design, setting α and β errors 0.05 and 0.10, 25 evaluable pts were required. The null hypothesis would have been rejected if at least 6 pts were progression free at 2 mos. Results: Between June 2011 and June 2012, 26 pts were enrolled. Main characteristics were: M/F 19/7; median age: 71 yrs; single/multiple sites of metastases: 2/24, KRAS wt/mut: 18/8, BRAFwt/mut 25/1. 16 (62%) pts had received at least 3 previous lines of chemotherapy. Five pts were progression free at 2 mos, for a 2m-PFR of 19%. At a median follow up of 14.4 mos, median PFS and OS were 2.1 and 6.0 mos. No chemo-related G3/4 adverse events were reported. Conclusions: Metronomic cape and CTX demonstrated low clinical activity in heavily pretreated mCRC. Ongoing pharmacokinetic and dynamic analyses might provide additional data to interpret results and further insights into the antiangiogenic properties of this metronomic combination. Clinical effects of metronomic cape and CTX are under investigation in earlier settings and in association with other antiangiogenic agents.
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Brandi, G., S. Fanello, F. Piscaglia, A. Falanga, L. Bolondi, S. Flori, E. Derenzini, E. Palassini, M. Fedele, and G. Biasco. "Metronomic capecitabine in advanced patients with hepatocellular carcinoma (HCC): Preliminary results." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 15163. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.15163.
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15163 Background: No standard therapies are available for HCC patients (pts) ineligible for curative treatments. HCC has a rich neovasculature and neoangiogenesis is a negative prognostic factor: a high density of microvessels and hyperexpression of VEGF correlates with an increased propensity for invasion and metastatization and with a decreased DFS after resection. High level of circulating endothelial progenitors cells (CEPc) are related with insurgence and progression of HCC. Phase II trials with antiangiogenic agents in monotherapy had a response rate lower than 10% but stable disease (SD) is encouraging ranging between 30 and 60%. Retrospective analysis of standard capecitibine showed a response of 11% and similar SD rate. Experimental data on solid tumors suggest that metronomic CT prolongs inibihition of tumor growth, avoiding CEPc mobilization. Methods: Starting in september 2006, twenty-two patients were started on treatment (19 male; median age 63.7, range 47–82 ). BCLC (Barcelona Consensus Liver Cancer): 5 pts = B; 17 pts = C; Child: 12 pts =A, 8=B, 2=C. 14 pts had portal thrombosis. 15 pts were treated in front line, 7 in second line (4 pts previously treated with Sorafenib and 3 with experimental protocol of CPT-11 HAI; ASCO 2006 Abs 14061 ). The first cycle was carried out with standard capecitabine (2000 mg/sq.mt; 14 over 21 days), followed by metronomic capecitabine (1300 mg) without interruption. To compare the angiogenic role of metronomic capecitabine versus standard administration, VEGF and trombospondine have been dosed at baseline and after the first cycle of standard capecitabine and after one month of metronomic capecitabine. The response has been assessed by CT scan every three months. Results: Five out of 22 patients have been dismissed for toxicity (liver failure) during the standard capecitabine treatment. Among the 17 remaining patients, two have discontinued the treatment due to toxicity (liver failure) during the metronomic treatment and 10 have accomplished at least the first month of metronomic schedule. 6 patients have been evaluated for response: 2 PR (one second line), 3 SD (all in second line), 1 PD (second line). Conclusions: Metronomic capecitabine seems to have a better tolerability than standard schedule and promises good efficacy. No significant financial relationships to disclose.
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Kumar, M. N. V. Ravi, and Anil K. Sood. "Editorial – Metronomic chemotherapy." Cancer Letters 400 (August 2017): 203. http://dx.doi.org/10.1016/j.canlet.2017.03.003.
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Sarmiento, Roberta, and Giampietro Gasparini. "Antiangiogenic Metronomic Chemotherapy." Onkologie 31, no. 4 (2008): 161–62. http://dx.doi.org/10.1159/000119925.
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Patil, Vijay M., Vanita Noronh, Amit Joshi, Ashay Karpe, Vikas Talreja, Arun Chandrasekharan, Sachin Dhumal, and Kumar Prabhash. "Metronomic palliative chemotherapy in maxillary sinus tumor." South Asian Journal of Cancer 05, no. 02 (April 2016): 056–58. http://dx.doi.org/10.4103/2278-330x.181626.
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Abstract Background: Metronomic chemotherapy consisting of methotrexate and celecoxib recently has shown promising results in multiple studies in head and neck cancers. However, these studies have not included patients with maxillary sinus primaries. Hence, the role of palliative metronomic chemotherapy in patients with maxillary sinus carcinoma that is not amenable to radical therapy is unknown. Methods: This was a retrospective analysis of carcinoma maxillary sinus patients who received palliative metronomic chemotherapy between August 2011 and August 2014. The demographic details, symptomatology, previous treatment details, indication for palliative chemotherapy, response to therapy, and overall survival (OS) details were extracted. SPSS version 16 was used for analysis. Descriptive statistics have been performed. Survival analysis was done by Kaplan-Meier method. Results: Five patients had received metronomic chemotherapy. The median age was 60 years (range 37-64 years). The proportion of patients surviving at 6 months, 12 months, and 18 months were 40%, 40%, and 20%, respectively. The estimated median OS was 126 days (95% confidence interval 0-299.9 days). The estimated median survival in patients with an event-free period after the last therapy of <6 months was 45 days, whereas it was 409 days in patients with an event-free period postlast therapy above 6 months (P = 0.063). Conclusion: Metronomic chemotherapy in carcinoma maxillary sinus holds promise. It has activity similar to that seen in head and neck cancers and needs to be evaluated further in a larger cohort of patients.
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Mpekris, Fotios, James W. Baish, Triantafyllos Stylianopoulos, and Rakesh K. Jain. "Role of vascular normalization in benefit from metronomic chemotherapy." Proceedings of the National Academy of Sciences 114, no. 8 (February 7, 2017): 1994–99. http://dx.doi.org/10.1073/pnas.1700340114.
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Metronomic dosing of chemotherapy—defined as frequent administration at lower doses—has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor–drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy.
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Hara, Tomohiko, Satoru Yoshihiro, Hideaki Ito, Kazuhiro Nagao, Chietaka Ohmi, Shigeru Sakano, Hideyasu Matsuyama, and Katsusuke Naito. "Metronomic Outpatient-Based Chemotherapy with 5′-DFUR and Low-Dose Cisplatin for Conventional Platinum-Based Chemotherapy-Resistant Advanced Urothelial Cancer." Clinical medicine. Oncology 1 (January 2007): CMO.S304. http://dx.doi.org/10.4137/cmo.s304.
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Background Metronomic chemotherapy is aimed at lessening the adverse effects of treatment while rendering cancer cells cytostatic. The oral 5-fluorouracil prodrug “5′-DFUR” has been shown to inhibit angiogenesis and is regarded as a good candidate agent for metronomic chemotherapy. Moreover, cisplatin and 5′-DFUR have been shown to synergistic cytotoxic effects. Methods We evaluated the safety and efficacy of metronomic chemotherapy using daily oral 5′-DFUR at the dose of 600 mg/day and biweekly cisplatin infusion at the dose of 20 mg/person in 23 patients with urothelial cancer resistant to conventional platinum-based chemotherapy. Results Twenty-three patients were enrolled between August 2000 and December 2004. The median survival time after the initiation of metronomic chemotherapy was 15.2 months. The 1-year, 2-year and 3-year survival rates were 55.1%, 45.1% and 5.9%, respectively. Grade 3 fatigue was observed as severe toxicity in one patient. No cases showed nephrotoxicity and adverse effects necessitating medical intervention. Conclusions Although a large-scale prospective study would be necessary before the therapy is established as a standard, our metronomic chemotherapy regimen appears to be a potentially useful palliative treatment alternative for patients with advanced urothelial cancer resistant to conventional platinum-based chemotherapy. Abbreviations M-VAC: methotrexate, vinblastine, doxorubicin, and cisplatin; GC: gemcitabine and carboplatin; 5′-DFUR: 5′-deoxy-5-fluorouridine; 5-FU: 5-fluorouracil; CDDP: cisplatin; TCC: transitional cell carcinoma; ECOG: Eastern Cooperative Oncology Group; PS: performance status; UICC: Union International Contre le Cancer; WHO: World Health Organization; NCI-CTC: National Cancer Institute Common Toxicity Criteria; CI: confidence interval; PR: partial response; NC: no change; PD: progressive disease; TP: thymidine phosphorylase; AUC: areas under the curve.
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Clarke, Jennifer L., Fabio M. Iwamoto, Joohee Sul, Katherine Panageas, Andrew B. Lassman, Lisa M. DeAngelis, Adília Hormigo, et al. "Randomized Phase II Trial of Chemoradiotherapy Followed by Either Dose-Dense or Metronomic Temozolomide for Newly Diagnosed Glioblastoma." Journal of Clinical Oncology 27, no. 23 (August 10, 2009): 3861–67. http://dx.doi.org/10.1200/jco.2008.20.7944.
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Purpose Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma (GBM) by increasing the therapeutic index, overcoming common mechanisms of temozolomide resistance, or both. The goal of this randomized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM. Patients and Methods Adult patients with newly diagnosed GBM were randomly assigned to receive standard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense (150 mg/m2 days 1 to 7 and 15 to 21) or metronomic (50 mg/m2 continuous daily) temozolomide. Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression. The primary end point was overall survival (OS) at 1 year. Tumor tissue was assayed to determine O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status. Results Eighty-five eligible patients were enrolled; 42 were randomly assigned to dose-dense and 43 to metronomic temozolomide. The 1-year survival rate was 80% for the dose-dense arm and 69% for the metronomic arm; median OS was 17.1 months (95% CI, 14.0 to 28.1 months) and 15.1 months (95% CI, 12.3 to 18.9 months), respectively. The most common toxicities were myelosuppression (leukopenia, neutropenia, and thrombocytopenia) and elevated liver enzymes. Pseudoprogression was observed in 37% of assessable patients and may have had an impact on estimates of progression-free survival (6.6 months in the dose-dense arm and 5.0 months in the metronomic arm). Conclusion Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity. The dose-dense regimen appears promising, with 1-year survival of 80%.
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Yeh, Tsung-Jang, Leong-Perng Chan, Hui-Ting Tsai, Chin-Mu Hsu, Shih-Feng Cho, Mei-Ren Pan, Yi-Chang Liu, et al. "The Overall Efficacy and Outcomes of Metronomic Tegafur-Uracil Chemotherapy on Locally Advanced Head and Neck Squamous Cell Carcinoma: A Real-World Cohort Experience." Biology 10, no. 2 (February 23, 2021): 168. http://dx.doi.org/10.3390/biology10020168.
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Metronomic chemotherapy inhibits tumor growth by continuous administration of lower-dose chemotherapy. Our study aimed to demonstrate the outcomes of metronomic chemotherapy with tegafur–uracil in locally advanced head and neck squamous cell carcinoma (LA HNSCC). This was a retrospective study including 240 patients with LA HNSCC. After standard treatment, 96 patients were further treated with metronomic tegafur-uracil, and 144 patients were not. No statistical differences were found between both groups with regard to sex, clinical stage, or primary treatment choice. There were more hypopharyngeal cancers and more patients with poor clinicopathological features, including lymphovascular invasion, extranodal extension, and positive margins in the tegafur–uracil group. The median follow-up duration was 31.16 months. Overall survival (OS) was not reached in the tegafur–uracil group and was 54.1 months in the control group (p = 0.008). The median disease-free survival (DFS) was 54.5 months in the tegafur–uracil group and 34.4 months in the control group (p = 0.03). Neither group reached distant metastasis-free survival (DMFS, p = 0.02). In patients with LA HNSCC, adding tegafur–uracil as metronomic chemotherapy after either curative surgery with adjuvant chemoradiotherapy or definitive concurrent chemoradiotherapy significantly improved the OS, DFS, and DMFS with tolerable adverse events.
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Abdelmaksoud, Bader A., Mostafa M. Toam, and Alaa A. Fayed. "Metronomic capecitabine with aromatase inhibitors for patients with metastatic hormone-receptor positive, HER2-negative breast cancer." Breast Cancer Management 8, no. 3 (November 1, 2019): BMT30. http://dx.doi.org/10.2217/bmt-2019-0012.
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Aim: To evaluate the efficacy and safety of combined metronomic capecitabine with aromatase inhibitors (AIs) for patients with newly diagnosed metastatic hormone-receptor positive, HER2-negative breast cancer. Patients & methods: A total of 41 women with a diagnosis of metastatic hormone-receptor positive, HER2-negative breast cancer received oral metronomic capecitabine, 500 mg/m2 twice daily combined with an AI. Results: After a median follow-up of 24 months (9–50), a median of 15 months of treatment were completed, the median time to progression was 15 months (12.6–17.3) and the median overall survival was 37 months (23.6–50.4). The treatment was tolerated with less than 10% grade 3 toxicities. Conclusion: Combination of metronomic capecitabine and AIs appears to be safe and has encouraging results in advanced hormone-receptor positive, HER2-negative breast cancer.
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Shaked, Yuval, Urban Emmenegger, Shan Man, Dave Cervi, Francesco Bertolini, Yaacov Ben-David, and Robert S. Kerbel. "Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity." Blood 106, no. 9 (November 1, 2005): 3058–61. http://dx.doi.org/10.1182/blood-2005-04-1422.
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Abstract Low-dose metronomic chemotherapy is a promising therapeutic cancer treatment strategy thought to have an antiangiogenic basis. However, the advantages of reduced toxicity, increased efficacy in some cases, and ability to combine chemotherapy administered long term in this way with targeted therapies can be compromised by the empiricism associated with determining the optimum biologic dose (OBD). Using 4 distinct metronomic chemotherapy regimens in 4 different preclinical tumor models, including a hematologic malignancy, we established the OBD by determining the maximum efficacy associated with minimum or no toxicity. We then found each OBD to be strikingly correlated with the maximum reduction in viable peripheral blood circulating vascular endothelial growth factor receptor 2–positive (VEGFR-2+) endothelial precursors (CEPs). These results suggest that CEPs may serve as a pharmacodynamic biomarker to determine the OBD of metronomic chemotherapy regimens.
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Kweon, Seho, Yoo-Seong Jeong, Yoon Gun Ko, Seung Woo Chung, Ha Kyeong Lee, Suk-Jae Chung, Youngro Byun, and Sang Yoon Kim. "Abstract 2730: Metronomic dose-finding approach of oral chemotherapy by experimentally-driven integrated mathematical modeling." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2730. http://dx.doi.org/10.1158/1538-7445.am2022-2730.
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Abstract Conventional chemotherapy with maximum tolerated dose (MTD) has shown confident anti-cancer effect and when combined with targeted therapy, immunotherapy. Yet, understanding about how the MTD regimen is optimized has lacked due to its high tumor burdens. In this study, the oral doxorubicin (DOX) formulation was shown to improve oral bioavailability by 12.1% and sustain the metronomic concentration through the flexible protocol. Since the optimizing dose and schedules of DOX in metronomic chemotherapy (MCT) is essential to maximize efficacy and minimize toxicity, which is determined by the exposure of drugs based on pharmacokinetic-pharmacodynamic (PK/PD) correlation, we developed an integrated systemic mathematical model that can evaluate the anti-tumor effect and the toxicity of oral DOX formulation simultaneously. Oral physiologically-based pharmacokinetic (PBPK) models were established with dose dependency, and creatine kinase-MB (CK-MB) and tumor growth profiles were assessed as markers for toxicodynamic (TD) and PD models, respectively. Each model was validated and then integrated into the PK-TD/PD model and the effects of various oral metronomic regimens were predicted. In conclusion, the finalized oral metronomic dosing regimen (10 mg/kg, QD) showed 83.3% tumor growth inhibition without cardiotoxicity. In this study, we defined the MCT regimen using a mathematical model and suggested a dose selection method for developing oral drugs from injections, to efficiently utilize the preclinical results and apply to clinical practice. Citation Format: Seho Kweon, Yoo-Seong Jeong, Yoon Gun Ko, Seung Woo Chung, Ha Kyeong Lee, Suk-Jae Chung, Youngro Byun, Sang Yoon Kim. Metronomic dose-finding approach of oral chemotherapy by experimentally-driven integrated mathematical modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2730.
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Pandey, Avinash, A. Desai, V. Ostwal, V. Patil, A. Kulkarni, R. Kulkarni, N. Patil, D. Chaukar, K. Prabhash, and Shripad D. Banavali. "Outcome of operable oral cavity cancer and impact of maintenance metronomic chemotherapy: A retrospective study from rural India." South Asian Journal of Cancer 05, no. 02 (April 2016): 052–55. http://dx.doi.org/10.4103/2278-330x.181625.
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Abstract Background: Oral cavity cancer is the most common cancer among rural India. There is a paucity of data for outcomes of operable oral cavity cancer from rural India. Use of maintenance metronomic may delay or avoid relapse. Aim: To evaluate outcomes of operable oral cavity carcinoma and evaluate impact of maintenance metronomic chemotherapy. Objectives: To evaluate disease-free survival (DFS), overall survival (OS), and factors affecting the outcome in operable oral cavity cancer. Materials and Methods: Data of patients diagnosed with oral cavity cancer registered between May 2008 and May 2014 were retrieved. Only those patients with operable oral cavity cancer and upfront definitive surgery were included in the study. Demographic profile, stage, tobacco consumption, adjuvant therapy, and pattern of failure were collected. Kaplan-Meir survival analysis was used to determine DFS and OS. Log-rank test was used to evaluate factors affecting outcome. Results: Median follow-up is 24 months. Out of 335 patients, 225 (67%) had advanced operable cancer with 42/225 (18%) and 183/225 (82%) as Stages III and IVA, respectively. Buccal mucosa was the most common subsite (178/335, 53%) followed by tongue (63/335, 19%). Ninety-two percent patients were addicted to smokeless tobacco, whereas 27% were smokers. Median DFS is 13 months with 2 years relative DFS 32%. Median OS is 30 months, with 2 years OS of 54%. Metronomic adjuvant oral chemotherapy was given in 130/225 (58%); Stage III and IVA patients with median of 14 months (3-18 months). Use of metronomic chemotherapy improved DFS (8 vs. 14 months, P = 0.22) and OS (14 vs. 26 months, P = 0.04). Conclusion: Oral cavity cancer is a major health care problem in rural India. Presentation at advanced stage leads to suboptimal outcomes. Benefit of metronomic maintenance chemotherapy in locally advanced oral cavity needs to be further evaluated prospectively.
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Carcamo, Benjamin, and Giulio Francia. "Cyclic Metronomic Chemotherapy for Pediatric Tumors: Six Case Reports and a Review of the Literature." Journal of Clinical Medicine 11, no. 10 (May 18, 2022): 2849. http://dx.doi.org/10.3390/jcm11102849.
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We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the kidney, one ependymoma, two medulloblastomas, one neuroblastoma, and a type II neurocytoma of the spine. Treatment included oral cyclophosphamide daily for 21 days alternating with oral etoposide daily for 21 days in a backbone of daily valproic acid and celecoxib. In one case, celecoxib was substituted with sulindac. Of the six patients, three showed complete responses, and all patients showed some response to metronomic therapy with only minor hematologic toxicity. One patient had hemorrhagic gastritis likely associated with NSAIDs while off prophylactic antacids. These data add to a growing body of evidence suggesting that continuous doses of valproic acid and celecoxib coupled with alternating metronomic chemotherapy of agents such as etoposide and cyclophosphamide can produce responses in pediatric tumors relapsing to conventional dose chemotherapy.
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André, Nicolas, Manon Carré, and Eddy Pasquier. "Metronomics: towards personalized chemotherapy?" Nature Reviews Clinical Oncology 11, no. 7 (June 10, 2014): 413–31. http://dx.doi.org/10.1038/nrclinonc.2014.89.
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Mazánková, Dana, Veronika Bárková, and Pavel Mazánek. "Metronomická terapie v léčbě nádorových onemocnění." Česká a slovenská farmacie 71, no. 3 (2022): 91–97. http://dx.doi.org/10.5817/csf2022-3-91.
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Metronomic therapy is a therapeutic method in selected oncological diseases, using long-term administration of low doses of drugs with direct or indirect antitumor effect. In addition, to direct cytotoxic eradication of tumor cells, metronomic therapy can very strongly affect the tumor microenvironment; it also has an immunomodulatory and antiangiogenic effect. Its minimal toxic profile allows for use in patients with severe organ dysfunctions and directly impacts the quality of life and social inclusion of oncological patients.
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Bilir, C., S. Durak, B. Kızılkaya, I. Hacıbekiroglu, E. Nayır, and H. Engin. "Efficacy of metronomic vinorelbine in elderly patients with advanced non-small-cell lung cancer and poor performance status." Current Oncology 24, no. 3 (June 28, 2017): 199. http://dx.doi.org/10.3747/co.24.3486.
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Background Metronomic chemotherapy—administration of low-dose chemotherapy—allows for a prolonged treatment duration and minimizes toxicity for unfit patients diagnosed with advanced non-small-cell lung cancer (nsclc).Methods Oral metronomic vinorelbine at 30 mg thrice weekly was given to 35 chemotherapy-naive patients who were elderly and vulnerable to toxicity and who had been diagnosed with advanced nsclc.Results Median age in this male-predominant cohort (29:6) was 76 years (range: 65–86 years). Histology was squamous cell carcinoma in 21 patients and adenocarcinoma in 14. There were no complete responses and 9 partial responses, for an overall response rate of 26%. Stable disease was seen in 15 patients (43%), and 11 patients (31%) had progressive disease. The 1-year survival rate was 34%, and the 2-year survival rate was 8%. The survival analysis showed a median progression-free survival duration of 4 months (range: 2–15 months) and an overall survival duration of 7 months (range: 3–24 months).Conclusions Metronomic vinorelbine had an acceptable efficacy and safety profile in elderly patients with multiple comorbidities who had been diagnosed with advanced nsclc. Metronomic vinorelbine could be a treatment option for elderly patients with poor performance status who are unfit for platinum-based chemotherapy and intravenous single-agent chemotherapy, and who are not candidates for combination modalities.
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Elsebaie, Hala, Wael Samir Makar Yassa, Shaimaa Lasheen, and Noha IbrahimIbrahim. "Efficacy, Safety and Cost Effectiveness of Metronomic Low Dose Versus Intermittent High Dose Capecitabine in Metastatic Breast Cancer." Open Access Macedonian Journal of Medical Sciences 9, B (October 3, 2021): 1048–53. http://dx.doi.org/10.3889/oamjms.2021.7089.
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AIM: The aim of the study is to compare the toxicity and cost-effectiveness between metronomic and intermittent capecitabine as maintenance therapy in female patients with metastatic breast cancer. PATIENTS AND METHODS: All metastatic breast cancer patients with HER2 negative were included. The whole study population received six cycles of Docetaxel/Capecitabine then patients were randomized to either continuous (650 mg/m2 twice daily continuous) or intermittent Capecitabine (1000 mg/m2 twice daily every 21 days) as maintenance. RESULTS: The study included 51 patients, 26 in the metronomic arm and 25 in the continuous. The median number of maintenance cycles, as well as the partial response, was higher in the continuous (18 vs. 13 cycles, p: 0.031; p: 0.038). The continuous arm was tolerable with significant less Grade 3 and 4 toxicity regarding nausea, vomiting, hand and foot syndrome, neutropenia, and elevated liver enzymes. (p: 0.03, 0.045, 0.051, 0.048, 0.06, respectively). On multivariate analysis, only patients receiving treatment as first-line had a better clinical response (p: 0.03) especially in the triple-negative group (p: 0.07). The metronomic therapy was more cost-effective with a 35.9% reduction of cost. ($ 746 vs. $1164). The progression-free survival and overall survival were not significant between the two groups. CONCLUSION: Metronomic continuous capecitabine proved to be less toxic and more cost-effective.
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Prabhash, K., V. Noronha, MV Krishna, V. Patil, A. Joshi, and SD Banavali. "Metronomic therapy: Chemotherapy revisited." Indian Journal of Cancer 50, no. 2 (2013): 142. http://dx.doi.org/10.4103/0019-509x.117027.
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Hatzimichael, E., and E. Briasoulis. "Metronomic chemotherapy beyond misconceptions." Haematologica 98, no. 11 (November 1, 2013): e145-e145. http://dx.doi.org/10.3324/haematol.2013.096917.
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Lee, Youngsik, and Dae-Hyeong Kim. "Wireless metronomic photodynamic therapy." Nature Biomedical Engineering 3, no. 1 (January 2019): 5–6. http://dx.doi.org/10.1038/s41551-018-0341-8.
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Lambrescu, Ioana, Simona Fica, Diana Martins, Francesca Spada, Chiara Cella, Emilio Bertani, Manila Rubino, et al. "Metronomic and metronomic-like therapies in neuroendocrine tumors – Rationale and clinical perspectives." Cancer Treatment Reviews 55 (April 2017): 46–56. http://dx.doi.org/10.1016/j.ctrv.2017.02.007.
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Laquente, B., C. Lacasa, M. Morell, O. Casanovas, A. Figueras, M. Galán, F. Viñals, G. Capella, and J. Germá. "Antitumoral effect of gemcitabine metronomic schedule in a xenograft pancreatic model." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 12031. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.12031.
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12031 Background: Human tumor xenografts in mice can be remarkably predictive of response in humans to cytotoxic chemotherapeutic drugs. Tumor endothelial cells are sensitive to the action of conventional cytotoxic drugs when they are regularly administrated at low doses. This concept, known as metronomic chemotherapy, has been demonstrated in preclinical studies using transplanted tumor models. We aim to investigate the potential anti-tumoral activity of Gemcitabine (G) when administered in a low-dose schedule in an ortothopic implantation model of human pancreatic carcinomas. Methods: Standard gemcitabine schedule: NP18 tumor orthotopically implanted nude mices were randomly distributed to experimental (n = 13, G100 mg/kg intraperitoneally on days 0, 3, 6 and 9 post-implantation) and control group (n = 13, saline). Animal were sacrificed after 4 weeks and we compared weigths (grams) and volume (cm3) of tumors betwen the two groups by the Mann-Whitney U test. Metronomic schedule: After a toxicological study an optimal metronomic dose of 1 mg G /kg per day was chosen. Thirty xenografted mices were randomly distributed to experimental group (n = 15, intraperitoneal G1 mg/kg) and control group (n = 15, saline) and treated for 30 days. Animal were analysed as described before. Results: Standard schedule: Tumor weight mean of treatment group was 0.01 grams ± 0.01 versus 0.54 grams ± 0.48 of the control group. Tumor volume mean in G group was 0.01 cm 3 ± 0.01 versus 0.51 cm 3 ± 0.67) in the control group.Treatment significantly inhibited NP18 tumour growth (p < 0.001). No differences in mice weight were observed between both groups. Metronomic schedule: Tumor weight mean in the treatment group was 0.04 grams ± 0.08 versus 0.53 grams ± 0.46 in control group. Tumor volume mean in G group was 011 cm 3 ± 0.19 versus 0.37 cm 3. Treatment with low-dose of G significantly inhibited NP18 tumour growth (p < 0.003). There were no differences in mice weight between the two groups. Conclusions: Our data show that G administered in a metronomic schedule is effective in inhibiting the growth of NP18 tumor orthotopically implanted in the nude mice. We now aim to study the angiogenic profile of tumors receiving the standard and metronomic schedule and to set up a new experiment to compare survival benefit in the animal model. No significant financial relationships to disclose.
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Ranade, Anantbhushan, Kanaka Govind Babu, Purvish M. Parikh, Jk Singh, Manisha Singh, and Gouri Shankar Bhattacharyya. "Efficacy and safety of metronomic capecitabine and gefitinib in heavily pretreated metastatic triple-negative breast cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1071. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1071.
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1071 Background: Metronomic chemotherapy regimens have shown efficacy in patients with metastatic breast cancer by antiangiogenic mechanisms. When used metronomically the toxicity profile of capecitabine is low. Triple negative breast cancer is a common problem in India and developing countries. Approximately 30% of triple negative breast cancer express EGFR and its mutation. Methods: Since October 2003 to December 2011 we objectively tested response rates, clinical benefit, and safety of gefitinib and capecitabine administered with a metronomic schedule of 500 mg thrice daily in heavily pretreated metastatic breast cancer patients with gefitinib 250 mg once daily. 300 patients were screened for EGFR expression. Among 85 enrolled patients with EGFR positivity, 76 were evaluable. ECOG performance status (PS) was 0-2, median age 52 years (range 36-65), bone plus visceral metastasis in 40% of patients. Rest had only visceral metastasis. All the patients were pretreated with anthracyclines and taxanes. The combination was administered for a median duration of 32 weeks (range 12-166). Results: We observed 18 partial responses (PR: 24%), 42 (55%) stable disease (SD). Median time to progression was 53 weeks, (95% CI, range 12-166 weeks). Safety of metronomic capecitabine with gefitinib was excellent. Neither grade 2-4 haematological or clinical side effects were recorded. Only 12 patients experienced grade I (WHO) hand-foot syndrome. Conclusions: Treatment with metronomic capecitabine and gefitinib was effective and minimally toxic in heavily pretreated breast cancer patients.
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DUSI, VIDYA SAGAR, Obul Reddy C, Suresh VS Attili, and Satya Dattatreya Palanki. "Gefitinb along with methotrexate as palliative therapy in PS 3 and above in metastatic esophagus squamous cell carcinoma with focus on Q-TWIST." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 355. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.355.
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355 Background: Metronomic therapy is proven method for treatment of terminally ill patients with malignancy, who are not fit for chemotherapy. The median PFS was significantly superior in responders in previous Indian experiences. However most of them were done in head and neck cancers.The prognosis of patients with metastatic esophageal cancer remains poor with only option being symptomatic care. As the previous experiences show metronomic therapy is safe among various options and there is no study focusing on Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) in southern Indian population,we thought of evaluating the same. Methods: Details of 42 subjects with refractory or progressive metastatic squamous cell carcinoma esophagus having PS > 2 were evaluated. Case records between 2017 September and 2018 September were analyzed for TWIST and QOL. Patients received Gefitinib (250 mg/day), Methotrexate 15 mg IM weekly or in combination. Patients were stratified into those with improved PS and those without. The subjects without PS improvement were continued on the single agent and those with improvement were offered additional chemotherapy based on physician/ patient preference. Metronomic therapy could be continued beyond disease progression- if there is TWIST/QOL improvement. Results: Out of 42 subjects, 29 had improvement in the PS and were continued later. 9 had stable PS and disease. 4 had worsening of PS. 34 subjects have clinically meaningful response (stable disease + complete + partial responses) and had symptomatic improvement. The median number of cycles was 6 (4–11). The median PFS was 198 days (95% CI, 174 to 214), and the median improvement in QOL was 6 points on a scale of 25. Grade II/IV toxicities were observed in 21 (50%) cases predominantly skin rash, stomatitis and diarrhea. Conclusions: Metronomic therapy is well tolerated and may have a role in the treatment of advanced cancers with poor performance status. 67% of the patients who are otherwise not eligible for any active therapy became eligible and had better QOL and longer PFS, which re-emphasizes role of metronomic therapy in advanced squamous cell carcinoma of esophagus.