preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survival
in advanced metastatic breast cancer in mice
ABSTRACT: Highly Efficacious Nontoxic Preclinical Treatment for Advanced Metastatic Breast Cancer Using Combination Oral UFT-Cyclophosphamide Metronomic Chemotherapy [Cancer Research; Subscribe]
Metronomic antiangiogenic chemotherapy, the prolonged administration of relatively low drug doses, at close regular intervals with no significant breaks, has been mainly studied at the preclinical level using single chemotherapeutic drugs, frequently in combination with a targeted antiangiogenic drug, and almost always evaluated on primary localized tumors. We tested a "doublet" combination metronomic chemotherapy treatment using two oral drugs, UFT, a 5-fluorouracil (5-FU) prodrug administered by gavage, and cyclophosphamide, for efficacy and toxicity in a new mouse model of advanced, terminal, metastatic human breast cancer. The optimal biological dose of each drug was first determined by effects on levels of circulating endothelial progenitor cells as a surrogate marker for angiogenesis, which was assessed to be 15 mg/kg for UFT and 20 mg/kg for cyclophosphamide. A combination treatment was then evaluated in mice with advanced metastatic disease using a serially selected metastatic variant of the MDA-MB-231 breast cancer-cell line, 231/LM2-4. UFT or cyclophosphamide treatment showed only very modest survival advantages whereas a combination of the two resulted in a remarkable prolongation of survival, with no evidence of overt toxicity despite 140 days of continuous therapy, such that a significant proportion of mice survived for over a year. In contrast, this striking therapeutic effect of the combination treatment was not observed when tested on primary orthotopic tumors. We conclude that combination oral low-dose daily metronomic chemotherapy, using cyclophosphamide and UFT, is superior to monotherapy and seems to be a safe and highly effective experimental antimetastatic therapy, in this case, for advanced metastatic breast cancer.
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
From above:
Quote:
UFT or cyclophosphamide treatment showed only very modest survival advantages whereas a combination of the two resulted in a remarkable prolongation of survival, with no evidence of overt toxicity despite 140 days of continuous therapy, such that a significant proportion of mice survived for over a year. In contrast, this striking therapeutic effect of the combination treatment was not observed when tested on primary orthotopic tumors. We conclude that combination oral low-dose daily metronomic chemotherapy, using cyclophosphamide and UFT, is superior to monotherapy and seems to be a safe and highly effective experimental antimetastatic therapy, in this case, for advanced metastatic breast cancer
Br J Cancer. 2003 Nov 3;89(9):1627-32. The potential for oral combination chemotherapy of 5'-deoxy-5-fluorouridine, a 5-FU prodrug, and cyclophosphamide for metastatic breast cancer.
Yoshimoto M, Tada K, Tokudome N, Kutomi G, Tanabe M, Goto T, Nishimura S, Makita M, Kasumi F.
Breast Oncology Group, Cancer Institute Hospital, Kami-Ikebukuro 1-37-1, Toshima-ku, Tokyo 170-8455, Japan. myoshimoto@jfcr.or.jp
Preclinical studies have demonstrated the synergistic anti-tumour activity of combination therapy with the oral cytostatics, 5'-deoxy-5-fluorouridine (5'-DFUR) and cyclophosphamide (CPA), in human breast cancer xenograft models. This study was performed to evaluate the efficacy and safety of this oral combination chemotherapy in the treatment of metastatic breast cancer. In all, 101 patients with metastatic breast cancer were enrolled in the study, and the data for 94 eligible patients of these were evaluated. The patients received twice daily oral combinations of 5'-DFUR (1200 mg/body/day) and CPA (100 mg/body/day) for 2 weeks, followed by a 1-week rest period. After a median of 19 treatment cycles (range 1-66 cycles), 16 patients (17.0%) had a complete response, and 40 patients (42.6%) had partial responses. The response rate was 59.6% (95% CI, 49.0-69.6%). The median time to progression and overall survival times were 11.7 and 40.3 months, respectively. The toxicity was mild and tolerable, and the related grade 3/4 clinical adverse effects consisted of haematological toxicity in 21 patients (22%) and nonhaematological toxicity in five patients (5%). These results suggest that the oral combination chemotherapy of 5'-DFUR and CPA has low toxicity and is a novel, very convenient and effective treatment for metastatic breast cancer.
PMID: 14583760 [PubMed - indexed for MEDLINE]
In Vivo. 2008 Nov-Dec;22(6):831-6. Low-dose oral metronomic chemotherapy prevents mobilization of endothelial progenitor cells into the blood of cancer patients.
Correspondence to: Stefan O. Peters, MD, Medizinische Klinik I, Haematologie, Ratzeburger Allee 160, 23538 Luebeck, Germany. Tel: +49 4515002669, Fax: +49 4515002410, e-mail: Stefan.Peters@UK-SH.de
Circulating endothelial progenitor cells (EPCs) actively supply cells that may participate in tumor angiogenesis. The differing effects of low-dose metronomic trofosfamide as opposed to conventional dose-dense chemotherapy on plasma levels of vascular endothelial growth factor (VEGF) and the numbers of circulating EPC are reported. Patients and Methods: Blood samples were obtained from cancer patients, 18 receiving oral metronomic chemotherapy of trofosfamide with or without celecoxib, and 24 receiving conventional dose-dense chemotherapy, eight of them in adjuvant intention. Mononuclear cells were analyzed by flow cytometry for CD34, CD45 and vascular endothelial growth factor-receptor 2 (VEGF-R2) coexpression, defining EPCs, and for plasma levels of VEGF by ELISA at day 0, 10 and 21 of therapy. Results: After conventional dose-dense chemotherapy, the numbers of circulating EPCs and the VEGF plasma concentrations increased sharply, doubling pretherapeutic levels at day 21. In contrast, under low-dose metronomic chemotherapy, the numbers of circulating EPCs decreased significantly and VEGF plasma concentrations remained unchanged. Conclusion: These observations provide evidence that conventional dose-dense chemotherapy leads to rebound EPC mobilization even when given with adjuvant intention, while low-dose metronomic scheduling of cytotoxic substances such as trofosfamide may sharply reduce EPC release into the circulation.
PMID: 19181016 [PubMed - indexed for MEDLINE]
Ann Oncol. 2008 Feb;19(2):212-22. Epub 2007 Nov 15. Effective oral chemotherapy for breast cancer: pillars of strength.
Findlay M, von Minckwitz G, Wardley A.
Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand. mp.findlay@auckland.ac.nz
Traditionally, anticancer therapy has been dominated by intravenous drug therapy. However, oral agents provide an attractive approach to chemotherapy and use of oral treatments is increasing. We discuss the benefits and challenges of oral chemotherapy from the perspectives of patients, healthcare providers and healthcare funders. Important issues include patient preference, efficacy, compliance, bioavailability, reimbursement, use in special patient populations, financial and staff time savings and flexibility of dosing. We review data for traditional oral agents (e.g. cyclophosphamide, methotrexate), newer oral chemotherapies (e.g. capecitabine), oral formulations of traditionally intravenous agents (e.g. vinorelbine, idarubicin) and new biologic agents under evaluation in breast cancer (e.g. tyrosine kinase inhibitors). Lastly, we review studies of all-oral combination regimens. The wealth of data available and the increasing use of oral agents in breast cancer suggest that many of the concerns and perceptions about oral therapy, including efficacy and bioavailability, have been overcome, and that oral therapy will play a major role in breast cancer management in the future in both the metastatic and adjuvant settings.
PMID: 18006898 [PubMed - indexed for MEDLINE]
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[SPACE RESERVED for metronomic CF+endocrine therapy.*]
[SPACE RESERVED for metronomic CF+Her2 therapy*]
[SPACE RESERVED for metronomic CF+endocrine therapy+Her2 therapy*]
*Add Metformin appropriate supplements and chronotherapy to all above
------------------------------------------------------------------------------------ BMC Cancer. 2006 Sep 15;6:225. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer.
Orlando L, Cardillo A, Ghisini R, Rocca A, Balduzzi A, Torrisi R, Peruzzotti G, Goldhirsch A, Pietri E, Colleoni M.
Unit of Research in Medical Senology, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. laura.orlando@ieo.it
BACKGROUND: HER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC). METHODS: Between April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks) in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week) and CTX (50 mg daily) (CM). RESULTS: The 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts), and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts), liver (14 pts), bone (12 pts), lymph nodes (8 pts), central nervous system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5-40%), 10 stable disease (SD) (46%, 95% CI 24-68%), and 8 PD (36%, CI 17-59%). The clinical benefit (RP plus RC plus SD for > or = 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24-68%) and 27% (95% CI, 6-61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade > or =2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively. CONCLUSION: The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.
PMID: 16978400 [PubMed - indexed for MEDLINE]
Bean counters rejoice:
Ann Oncol. 2005 Aug;16(8):1243-52. Epub 2005 May 19. Cyclophosphamide-methotrexate 'metronomic' chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation.
Bocci G, Tuccori M, Emmenegger U, Liguori V, Falcone A, Kerbel RS, Del Tacca M.
Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies, University of Pisa, Via Roma, Pisa, Italy. g.bocci@med.unipi.it
BACKGROUND: Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks-is a potentially novel approach to the control of advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has, as an advantage, the property of significantly reducing undesirable toxic side-effects. The aim of the present study was to evaluate the cost effectiveness of cyclophosphamide-methotrexate 'metronomic' chemotherapy in the palliative treatment of pretreated metastatic breast cancer. METHODS: Low-dose cyclophosphamide-methotrexate 'metronomic' chemotherapy was compared with outcome and resource utilisation data of published phase II trials regarding metastatic breast cancer, performed in western countries, mostly in Europe. All direct costs associated with metastatic breast cancer treatment were included and adjusted to year 2003 values. Sensitivity analyses were performed and variations to the values of key parameters were assessed. RESULTS: Low-dose cyclophosphamide-methotrexate 'metronomic' therapy was assessed to be a cost-effective/cost-saving therapy for palliative treatment for metastatic breast cancer when compared with novel chemotherapy strategies (phase II trials). Compared with the 11 phase II mono- and combination chemotherapies, metronomic treatment showed marked cost savings in each case and improved cost effectiveness. Sensitivity analyses showed the results were robust to variations to the values of key parameters with very few exceptions. CONCLUSIONS: Metronomic cyclophosphamide-methotrexate is significantly cost effective. If validated by prospective randomized trials, the treatment concept could reduce healthcare costs, especially those associated with the combined use of new, highly expensive, molecularly targeted therapies.
PMID: 15905308 [PubMed - indexed for MEDLINE]
Mol Cancer Ther. 2009 Oct;8(10):2872-81. Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models.
Daenen LG, Shaked Y, Man S, Xu P, Voest EE, Hoffman RM, Chaplin DJ, Kerbel RS.
Molecular and Cell Biology Research, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada. Vascular disrupting agents preferentially target the established but abnormal tumor vasculature, resulting in extensive intratumoral hypoxia and cell death. However, a rim of viable tumor tissue remains from which angiogenesis-dependent regrowth can occur, in part through the mobilization and tumor colonization of circulating endothelial progenitor cells (CEP). Cotreatment with an agent that blocks CEPs, such as a vascular endothelial growth factor pathway-targeting biological antiangiogenic drug, results in enhanced antitumor efficacy. We asked whether an alternative therapeutic modality, low-dose metronomic chemotherapy, could achieve the same result given its CEP-targeting effects. We studied the combination of the vascular disrupting agent OXi4503 with daily administration of CEP-inhibiting, low-dose metronomic cyclophosphamide to treat primary orthotopic tumors with the use of the 231/LM2-4 breast cancer cell line and MeWo melanoma cell line. In addition, CEP mobilization and various tumor characteristics were assessed. We found that daily p.o. low-dose metronomic cyclophosphamide was capable of preventing the CEP spike and tumor colonization induced by OXi4503. This was associated with a decrease in the tumor rim and marked suppression of primary 231/LM2-4 growth in nude as well as severe combined immunodeficient mice. Similar results were found in MeWo-bearing nude mice. The delay in tumor growth was accompanied by significant decreases in microvessel density, perfusion, and proliferation, and a significant increase in tumor cell apoptosis. No overt toxicity was observed. The combination of OXi4503 and metronomic chemotherapy results in prolonged tumor control, thereby expanding the list of therapeutic agents that can be successfully integrated with metronomic low-dose chemotherapy.
PMID: 19825805 [PubMed - in process]
Breast. 2009 Oct;18S3:S41-S47. Issues regarding improving the impact of antiangiogenic drugs for the treatment of breast cancer.
Kerbel RS.
Department of Molecular & Cellular Biology Research, Sunnybrook Health Sciences Centre, S-217, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
One of the major recent clinical advances in cancer treatment is the use of antiangiogenic drugs such as bevacizumab, sorafenib, and sunitinib. Bevacizumab, the monoclonal anti-VEGF antibody, has been approved for the first line treatment of metastatic breast cancer (MBC) when combined with taxane. However, the clinical benefits are modest; despite a doubling of response rates and significant prolongation of progression free survival times, no increase in overall survival is attained. This review summarizes some of the possibilities to account for this discrepant result. These include rapid development of acquired drug resistance due to the redundancy of proangiogenic growth factors, acceleration of tumor growth after antiangiogenic drug treatments are stopped, and increases in tumor cell malignant aggressiveness driven by mechanisms such as increased tumor hypoxia. Some possible strategies to improve the benefits of antiangiogenic drug therapy are discussed such as prolonging the treatment beyond tumor progression, combination with other therapeutic modalities, e.g. long term ('maintenance') low-dose metronomic chemotherapy or additional targeted/biologic drugs, e.g. trastuzumab.
PMID: 19914541 [PubMed - as supplied by publisher]
Oncology. 2010 Jan 11;77(6):358-365. [Epub ahead of print] Safety, Tolerability and Biological Effects of Long-Term Metronomic Administration of Non-Cytotoxic Anti-Angiogenic Agents.
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
Yes, I just heard Dr. Kerbel speak on a similar protocol at the San Diego conference I attended mid-October.
Among what he discussed:
Clin Cancer Res. 2009 Oct 15;15(20):6358-66. Epub 2009 Oct 13.
Comparative impact of trastuzumab and cyclophosphamide on HER-2-positive human breast cancer xenografts.
Francia G, Man S, Lee CJ, Lee CR, Xu P, Mossoba ME, Emmenegger U, Medin JA, Kerbel RS.
Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada. robert.kerbel@sri.utoronto.ca
Comment in:
Clin Cancer Res. 2009 Oct 15;15(20):6311-3.
PURPOSE: Metronomic chemotherapy is a minimally toxic and frequently effective new treatment strategy that is beginning to show promising phase II clinical trial results, particularly for metastatic breast cancer when combined with various molecularly targeted antitumor agents. Here, we assessed a treatment strategy that uses trastuzumab plus daily oral metronomic cyclophosphamide on metastatic Her-2-positive human breast cancer models. EXPERIMENTAL DESIGN: Treatments were initiated on orthotopic transplanted primary tumors as well as established visceral metastatic disease of two independent Her-2-positive breast cancer models, both independently derived from the human MDA-MB-231 breast cancer cell line. Outcome was assessed by noninvasive measurements of tumor cell-secreted human choriogonadotropin in the urine as a surrogate marker of relative tumor burden, or by whole body bioluminescent imaging, in addition to prolongation of survival. RESULTS: Orthotopic primary tumors responded to trastuzumab monotherapy with significant growth delays, whereas minimal antitumor effect was observed when mice with metastatic disease were treated. Nevertheless, trastuzumab showed a benefit in this latter setting when combined with metronomic low-dose cyclophosphamide as assessed by prolongation of survival. This benefit was similar to trastuzumab plus maximum tolerated dose cyclophosphamide, but was associated with lesser toxicity. CONCLUSIONS: Trastuzumab combined with metronomic cyclophosphamide may be an effective long-term maintenance strategy for the treatment of Her-2-positive metastatic breast cancer.
Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g., paclitaxel, can rapidly induce proangiogenic bone marrow-derived circulating endothelial progenitor (CEP) mobilization and subsequent tumor homing, whereas others, e.g., gemcitabine, do not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1alpha and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or paclitaxel treatment in CEP-deficient Id mutant mice, both of which resulted in enhanced antitumor effects mediated by paclitaxel, but not by gemcitabine.
PMID: 18772115
Especially interesting since there are others pointing out that antimitotics can trigger undesirable activities. Paclitaxel is an antimitotic, Gemcitabine is an antimetabolite. http://her2support.org/vbulletin/sho...ht=antimitotic
But maybe metronomic delivery of all drugs reduces this?: Metronomic Chemotherapy Have Opposite Effects on the Mobilization and Viability of Circulating Endothelial Progenitor Cells1
Francesco Bertolini2, Saki Paul, Patrizia Mancuso, Silvia Monestiroli, Alberto Gobbi, Yuval Shaked and Robert S. Kerbel Division of Hematology-Oncology, Department of Medicine [F. B., S. P., P. M.] and Department of Experimental Oncology, IFOM-Fondazione Italiana per la Ricerca sul Cancro Institute of Molecular Oncology [S. M., A. G.], European Institute of Oncology, 20141 Milan, Italy; Molecular and Cell Biology Research, Sunnybrook and Women’s College Health Sciences Centre, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M4N 3M5 Canada [Y. S., R. S. K.]
There is growing evidence that vasculogenesis (progenitor cell-derivedgeneration of new blood vessels) is required for the growthof some neoplastic diseases. Here we show that the administrationof cyclophosphamide (CTX) at the maximum tolerable dose with21-day breaks or at more frequent low-dose (metronomic) scheduleshave opposite effects on the mobilization and viability of circulatingendothelial progenitors (CEPs) in immunodeficient mice bearinghuman lymphoma cells. Animals treated with the maximum tolerabledose CTX experienced a robust CEP mobilization a few days afterthe end of a cycle of drug administration, and tumors rapidlybecame drug resistant.CTX was associated with a consistent decrease in CEP numbersand viability and with more durable inhibition of tumor growth. Conversely, the administration of metronomicOur findings suggest that metronomic low-dose chemotherapy regimensare particularly promising for avoiding CEP mobilization and,hence, to potentially reduce vasculogenesis-dependent mechanismsof tumor growth.
and...maybe the process observed isn't important:
Int J Cancer. 2009 Oct 15;125(8):1771-7. Endothelial progenitor cells do not contribute to tumor endothelium in primary and metastatic tumors.
Wickersheim A, Kerber M, de Miguel LS, Plate KH, Machein MR.
Tumor Angiogenesis Research Group, Department of Neurosurgery, University of Freiburg Medical School, D-79106 Freiburg, Germany.
Despite extensive research, the contribution of bone-marrow-derived endothelial progenitor cells (BM-EPC) to tumor angiogenesis remains controversial. In previous publications, the extent of incorporation of BM-EPCs into the endothelial cell (EC) layer in different tumor models has been reported as significant in some studies but undetectable in others. Here, we studied the differentiation of BM-EPCs and its contribution to tumor vessels in experimental and spontaneous lung metastasis (B16 melanoma and prostate carcinoma), in an autochthonous transgenic model of prostate tumorigenesis, in orthotopically implanted lung tumors [Lewis lung carcinoma (LLC)], in heterotopic subcutaneous models (LLC and C1 prostate carcinoma) growing in green fluorescent protein (GFP)-expressing bone marrow (BM) chimeras. Immunofluorescence was performed with a set of endothelial and hematopoietic markers and confocal microscopy was used to generate 3D reconstruction images. By performing rigorously conducted morphological studies, we found no evidence of BM-EPCs differentiation into tumor endothelium independently of tumor type, grade and organ site in primary and metastatic tumors. The vast majority of GFP(+) cells were trafficking leucocytes or periendothelial myeloid cells. To explore the possibility that local overexpression of vascular endothelial growth factor (VEGF) might increase the numbers of incorporated BM-EPCs, we analyzed tumors genetically manipulated to overexpress VEGF(164). Local VEGF production induces a massive infiltration of bone-marrow-derived cells, but did not lead to vessel wall integration of these cells. Collectively, these findings suggest that during tumor progression vascularization occurs primarily via classical tumor angiogenesis (e.g., sprouting of pre-existing ECs), whereas BM-EPCs do not incorporate into the vessel wall to any significant extent.
Although not typically considered a "targeted therapy" along the lines of drugs like trastuzumab (Herceptin) or gefitinib (Iressa), most chemotherapy does have a general target: rapidly dividing cells. This description applies well to cancer cells but, unfortunately, also describes some healthy cells, such as those in the bone marrow or gut, which also draw chemotherapy's wrath.
But chemotherapy drugs also have another target: endothelial cells that form the lining of newly formed blood vessels, such as those whose creation is orchestrated by tumors to fuel their growth. There is a considerable body of evidence that even very low, nontoxic doses of chemotherapy drugs, when delivered frequently for a prolonged period of time, can retard tumor blood vessel growth (or angiogenesis) by destroying endothelial cells.
Treatment approaches along these lines are now being tested in clinical trials, and they've been coined metronomic chemotherapy.
"The definition of metronomic chemotherapy varies, but generally it refers to repetitive, low doses of chemotherapy drugs designed to minimize toxicity and target the endothelium or tumor stroma as opposed to targeting the tumor," says Dr. Harold J. Burstein of the Dana-Farber Cancer Institute, who has led several early-stage trials of metronomic chemotherapy in women with breast cancer.
"It's definitely an interesting approach that opens up the possibility of using chemotherapy differently than we have traditionally considered," says Dr. Burstein.
The metronomic approach was initially proposed and tested in animal models by Dr. Timothy Browder in Dr. Judah Folkman's lab at Harvard Medical School. In the studies, standard maximum-tolerated dose (MTD) chemotherapy regimens caused cell death of endothelial cells in the blood vessels feeding to the tumor first, followed by tumor cells. But the long breaks needed between the MTD regimens allowed the damaged blood vessels, and thus the tumor, to recover.
But significantly lower doses given more frequently on a prolonged schedule proved to be far more effective, including complete tumor regressions, even in mice that were resistant to the same drug when used in a standard MTD regimen.
Since then, several research groups have confirmed these findings. And studies conducted in cell lines and animal models have also suggested that combining metronomic chemotherapy with targeted anti-angiogenesis agents is more effective than metronomic chemotherapy alone.
"I think the preclinical data together with the clinical trial results seen so far make a strong argument for testing metronomic chemotherapy more aggressively in larger trials, including trials where it's combined with different targeted agents," argues Dr. Robert Kerbel, of Sunnybrook Health Sciences Centre in Toronto, who has led many preclinical studies of metronomic chemotherapy.
A true metronomic regimen of frequent, low-dose chemotherapy over a longer period has yet to be tested in any phase III trials in the United States. A number of phase I and II trials have been conducted, however, yielding some provocative, if not altogether convincing, results. Dr. Burstein presented data last December from a phase II clinical trial comparing a common metronomic regimen - a daily low dose of oral cyclophosphamide and a low dose of methotrexate twice a week - with or without the targeted anti-angiogenesis drug bevacizumab. The combination approach was superior to metronomic chemotherapy alone in delaying disease progression, but was not necessarily an improvement upon the results typically seen in similar patient populations treated with a standard MTD regimen.
Concerns about the toxic effects of conventional cancer treatments on pediatric patients also has prompted pediatric oncology researchers to investigate metronomic-like approaches to treatment. Some promising early results have been reported.
Based on the available clinical evidence, says Dr. Burstein, it's unclear in what setting metronomic chemotherapy might prove most useful. "Those who are enthusiastic about it think it can be used anywhere," he says. "I think it's most likely to be used to treat more indolent, less threatening tumors because it may not work fast enough for those…with more aggressive disease."
Researchers like Dr. Kerbel, meanwhile, are making some headway on better understanding the nuts and bolts of metronomic chemotherapy, such as how to determine the lowest dose that can provide a potent benefit - the so-called optimal biological dose - and identifying biological markers that demonstrate whether the approach is having an anti-angiogenic effect. Then there's this question: Can chemotherapy be delivered more frequently, even daily, at significantly higher doses than those used in most metronomic regimens but less than in MTD regimens? The toxicity might be greater than a "traditional" metronomic regimen, but so might the effectiveness, including in comparison with standard MTD regimens. That's exactly what was shown in a phase III clinical trial presented earlier this month at the ASCO annual meeting. In women with locally advanced or inflammatory breast cancer, a presurgical (or neoadjuvant), metronomic-like regimen - using higher doses of cyclophosphamide, given daily; doxorubicin; and growth factor support to ensure the continued production of white blood cells - was superior to a standard MTD regimen at eliminating evidence of invasive cancer at the time of surgery. This outcome, explains Dr. Robert Livingston, a co-investigator on the Southwest Oncology Group-led trial, generally has been found to predict superior long-term outcome in patients.
The idea, according to Dr. Livingston, is to try to expose tumor cells to minimum concentrations of chemotherapy drugs for as long as possible.
"I think it's fair to call the regimen we have developed a hybrid," he says. "It can destroy tumor cells and, at the same time, the continuous exposure, particularly to cyclophosphamide, is having an anti-angiogenic effect." By Carmen Phillips
....Ultimately, lasting eradication of malignancy, as well as prevention of malignancy in the first place, depends solely upon competent immune function. Cytoreductive strategies, such as radio-or chemotherapy, serve their intended purpose of rapid tumor reduction but are hopeless at creating or even enabling a full endogenous immunological response. Unsurprisingly, then, such therapies diminish self-defense mechanisms leaving the host susceptible not only to infectious disease, but to recurrence and metastasis of their cancer as well.
...When angiogenesis is inhibited, cells become deprived of necessary nutrients including oxygen. When this occurs, the cells begin to go through the process of apoptosis,14 or programmed cell death. When cells become apoptotic, they begin to display certain markers on their cell surface.20 Phosphatidyl serine, normally located on the cytosolic aspect of the phospholipid bilayer membrane and the most immunologically important membrane-bound molecule, becomes displayed on the extracellular surface during the apoptotic event. The phosphatidyl serine then serves as a signal to phagocytic cells to approach and then engulf the apoptotic cell.
Promiscuously, as the phagocytic cell engulfs the apoptotic cell, the TSA is engulfed as well. Once inside the phagocytic cell, the TSA becomes recognized and processed the same way it would be if free TSA (tumor-specific antigen) were taken up by the phagocyte. In this way, angiogenesis inhibition is a form of indirect immunotherapy via augmentation of the membrane characteristics of the cancer cell.
Microfractionated Chemotherapy
As mentioned at the beginning of this article, specific activation of the immune system against an autologous tumor associated antigen is the ultimate route to preventing relapse of a malignancy. During times when a patient has a large tumor volume, this route of treatment is too slow to act. Thus, a more quickly acting metabolic-debulking strategy is necessary. In this way, as mentioned above, the tumor cells become more immunogenic. For this reason, MCT is usually potentiated with biological response modification (BRMP) with the use of immunothera-Microfractionated
chemotherapy (MCT) represents such a modality wherein conventional cytotoxic agents are utilized at non-cytotoxic doses.
Three main purposes are served in this model; when delivered via the microfractionation method conventional agents can be: 1) antiangiogenic; 2) pro-apoptotic; and 3) immuno-stimulatory.
Three conventional agents have recently been shown to have angiogenic
inhibitory qualities, namely docetaxel and paclitaxel (taxanes) and vinflunine, a vinca alkaloid.21-22 As above, angiogenesis inhibition will also result in a pro-apoptotic effect on the tumor cells. MCT provides a general treatment contrast to traditional dosing of the same agents in that the goal of the traditional treatment is to eradicate the tumor cells quickly while the goal of the microfractionation method is to induce a subtle but constant apoptotic effect.
In this way, as mentioned above, the tumor cells become more immunogenic. For this reason, MCT is usually potentiated with biological
response modification (BRMP) with the use of immunothera-peutic and other agents. As the induction of a specific anti-TSA immune response is not immediate, the MCT model enables survival of the patient to the time when such a response can be elicited.23 By using the microfracitonation method the immune systems of patients are left intact thereby able to be stimulated either by immune therapy or by some other mechanism.
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
Breast. 2009 Oct 31. [Epub ahead of print] Metronomic administration of pegylated liposomal-doxorubicin in extensively pre-treated metastatic breast cancer patients: A mono-institutional case-series report.
Munzone E, Di Pietro A, Goldhirsch A, Minchella I, Verri E, Cossu Rocca M, Marenghi C, Curigliano G, Radice D, Adamoli L, Nolè F.
Division of Medical Oncology, European Institute of Oncology, via Ripamonti, 435, 20141 Milan, Italy.
BACKGROUND: Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. Pegylated liposomal-doxorubicin (PLD) pharmacokinetic characteristics support the rationale for using the drug in a metronomic fashion, potentially able to combine anthracyclines efficacy to a low toxicity profile. PATIENTS AND METHODS: In a case-series report carried out in both anthracycline-naive and pre-treated metastatic breast cancer patients, we tested feasibility, clinical efficacy and tolerability of PLD administered with a novel metronomic schedule of 20mg/m(2) i.v. every two weeks. RESULTS: 52 patients were enrolled and 45 were evaluated. Forty-four patients were assessed for either response or toxicity. Eight patients (18%) had partial responses (PR) and 17 (39%) stable disease (SD), with a clinical benefit (CB) of 45% (95% CI: 30.3%-59.7%). Nineteen patients (43%) had progressive disease (PD). Neither grade 3 nor grade 4 haematological or clinical side effects were recorded, except for 2 patients with grade 3 palmar-plantar erythrodysesthesia (PPE). No cardiac toxicity was recorded. CONCLUSION: Metronomic administration of PLD is a feasible and active treatment for extensively pre-treated metastatic breast cancer patients, alternative to classic anthracyclines, balancing clinical efficacy with a good quality of life in terms of reduced side effects and low personal costs for the patient.
PMID: 19884008 [PubMed - as supplied by publisher]
J Clin Oncol. 2006 Aug 1;24(22):3623-8. Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients.
Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S, Allevi G, Aguggini S, Bodini G, Milani M, Dionisio R, Bernardi C, Montruccoli A, Bruzzi P, Harris AL, Dogliotti L, Berruti A.
Breast Unit and Anatomia Patologica, Azienda Ospedaliera Istituti Ospitalieri Cremona, Italy.
PURPOSE: To investigate the activity of letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment (PST) in elderly breast cancer patients. METHODS: One hundred fourteen consecutive elderly women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to primary letrozole therapy (2.5 mg daily for 6 months) or a combination of letrozole plus oral cyclophosphamide (50 mg/daily for 6 months) in an open-labeled, randomized phase II trial. Tumor response was assessed clinically, and tumor Ki67 index and vascular endothelial growth factor (VEGF) -A levels were measured before and after treatment. RESULTS: Overall response rate was 71.9% (95% CI, 60.0 to 83.8) in the 57 patients randomly assigned to receive primary letrozole and 87.7% (95% CI, 78.6 to 96.2) in the 57 patients randomly assigned to receive letrozole plus cyclophosphamide. The difference in activity between treatment arms was predominantly confined to patients with ductal histology. There was a significantly greater suppression of Ki67 and VEGF-A expression in the letrozole/cyclophosphamide-treated group than in the letrozole-treated group, leading to lower Ki67 and VEGF expression at post-treatment residual histology (P = .03 and P = .002, respectively). CONCLUSION: Both letrozole and letrozole plus cyclophosphamide treatments appeared active as PST in elderly breast cancer patients. Metronomic scheduling of cyclophosphamide may have an antiangiogenic effect and the combination of letrozole plus cyclophosphamide warrants testing in a randomized phase III trial.
PMID: 16877730 [PubMed - indexed for MEDLINE]
Quote:
Chemotherapy efficacy is dependent mainly on proliferative activity, whereas endocrine therapies are cytostatic, so that an antagonistic interaction between the two treatment modalities is expected when they are administered concomitantly.14 The results of a large randomized clinical trial published recently are in line with these assumptions.15
Because the target of the metronomic chemotherapy is not the proliferating cancer cells, this treatment modality could potentiate the efficacy of endocrine therapy.
Quote:
In this article, we explored the activity of the combination of LET-CYC administration as PST in elderly breast cancer patients as compared to standard LET. The response rate of 72% in patients randomly assigned to the LET arm was higher than the 60% obtained in a previous randomized trial with primary LET therapy.2 The different patient population and the longer exposure of our patients to LET (6 months v 4 months) can account for the observed difference. The response rate obtained in the LET-CYC arm(88%) was high.
The study design was not aimed at testing the difference in response rates in the two treatment arms, and both passed the test of activity. However, the comparison with the randomized control arm indicates that the high activity of the experimental arm was not caused by a biased sample,22 and suggests that the addition of CYC is associated with an increase in the activity of LET in this patient population (OR, 2.79). Although these results are encouraging, they failed to be confirmed by pathCR, a known predictor of long-term outcome. pathCR was observed in two patients (3.5%), one in each arm. A very low pathCR with primary LET therapy (1.7%) was obtained in the randomized trial comparing LET versus tamoxifen,2 suggesting that this condition is not a sensitive end point for primary endocrine therapy. The addition of metronomic CYC failed to increase the pathCR rate. Others have also found that patients with ER tumors have a low propensity to obtain pathCR after chemotherapy.23,24
Novel antivascular efficacy of metronomic docetaxel therapy in prostate cancer: hnRNP K as a player
1Oncologia Molecolare, Istituto Nazionale per la Ricerca sul Cancro, Largo R.Benzi 10, 16132 Genova, Italy 2Tumori Urologici, Istituto Nazionale per la Ricerca sul Cancro, Largo R.Benzi 10, 16132 Genova, Italy
*Correspondence to Nicoletta Ferrari, Oncologia Molecolare, Istituto Nazionale per la Ricerca sul Cancro, L.go R.Benzi 10, 16132 Genova, Italy Fax: +39-010-573-7409. Funded by: Ministero della Salute (2005-conv 93) Compagnia di San Paolo
Cancer Treat Rev. 2009 Nov 26. [Epub ahead of print] Overall survival benefit for weekly vs. three-weekly taxanes regimens in advanced breast cancer: A meta-analysis.
Mauri D, Kamposioras K, Tsali L, Bristianou M, Valachis A, Karathanasi I, Georgiou C, Polyzos NP.
Department of Medical Oncology, General Hospital of Lamia, Lamia, Greece; Panhellenic Association for Continual Medical Research (PACMeR), Greece.
BACKGROUND: Taxanes have been extensively tested in patients with advanced breast cancer, but it is unclear whether their weekly use might offer any benefits against standard every three weeks administration. We therefore performed a meta-analysis of randomized controlled trials that compared weekly and every three weeks taxanes regimens in advanced breast cancer. METHODS: The endpoints that we assessed were objective response rate, progression free survival (PFS) and overall survival. Efficacy data for paclitaxel and docetaxel were separately analyzed. Trials were located through PubMed and Cochrane Library searches and abstracts of major international conferences. RESULTS: Omicronbjective response rate was notably better when paclitaxel was used as every three weeks regimen (7 studies, 1772 patients, fixed effect model pooled RR 1.20 95%CI 1.08-1.32 p<0.001). No difference were found for PFS (6 studies, 1610 patients, random effect model HR 1.02, 95%CI 0.81-1.30 p=0.860); while OS was statistically higher among patients receiving weekly paclitaxel (5 studies, 1471 patients, fixed effect model pooled HR 0.78, 95%CI 0.67-0.89 p=0.001). No differences were observed for the weekly compared to the every three weeks use of docetaxel either for objective response, PFS and OS. Overall, the incidence of serious adverse events, neutropenia, neutropenic fever, and peripheral neuropathy were significantly lower in weekly taxanes schedules. The incidence of nail changes and epiphora were significantly lower in the every three weeks docetaxel regimens. CONCLUSIONS: Use of paclitaxel in weekly regimen give overall survival advantages compared with the standard every three weeks regimen. The observed survival benefit does not seem to stem from an increased potency of the drug with weekly regimens. The use of weekly paclitaxel regimens is therefore recommended for the treatment of locally advanced/metastatic breast cancer.
PMID: 19945225 [PubMed - as supplied by publisher]
Robert S. Kerbel; Barton A. Kamen
Published: 06/18/2004
Abstract
In addition to proliferating cancer cells and various types of normal cells, such as those of the bone marrow, conventional cytotoxic chemotherapeutics affect the endothelium of the growing tumour vasculature. The anti-angiogenic efficacy of chemotherapy seems to be optimized by administering comparatively low doses of drug on a frequent or continuous schedule, with no extended interruptions — sometimes referred to as 'metronomic' chemotherapy. In addition to reduced acute toxicity, the efficacy of metronomic chemotherapy seems to increase when administered in combination with specific anti-angiogenic drugs. Gaining better insight into the mechanisms of these effects could lessen or even eliminate the empiricism used to determine the optimal dose and schedule for metronomic chemotherapy regimens.
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The combination of cyclophosphamide and methotrexate has already been tested in a clinical trial in Italy, and has spurred additional trials that are underway.[49]Sixty-four women with progressive, advanced and refractory breast cancer received low doses of oral cyclophosphamide on a daily basis and oral methotrexate was given twice per week. Most of the patients had progressive metastatic disease when the trial began and had also previously received first-, second- or third-line treatments. An overall response rate of 32% was observed, which included two complete responders, 10 partial responders and 12 patients with stable disease lasting 6 months or longer.[49] No high-grade adverse events were reported, despite the fact that many patients had previously been treated with chemotherapy. This compares favorably with the standard third-line chemotherapy regimens used in this treatment setting, at least in terms of toxicity. The estimated cost of this outpatient therapy was about US$10 per month.[49]
Phase II clinical trials have been initiated to test the possible benefits of metronomic chemotherapy regimens — particularly when these are combined with an anti-angiogenic drug. Several of these trials are summarized in Table 3 . Most of these involve chemotherapy regimens in which cyclophosphamide is administered orally on a daily basis, sometimes for up to 2 years, with no break periods. In some cases, oral low-dose methotrexate is also given on two consecutive days on a weekly basis. The targeted drugs that are used include a cyclooxygenase-2 (COX2)-specific inhibitor such as celecoxib, which is administered on a daily basis, or a humanized anti-VEGF monoclonal antibody (such as bevacizumab), which is administered intravenously every 2 weeks.Celecoxib was selected for inclusion in the trial because of its commercial availability, ease of administration, excellent side-effect profile and putative anti-angiogenic effects.[101,102]
METRONOMIC CHEMOTHERAPY can be viewed as a variation of dose-dense therapy with the exception that the cumulative dose with metronomic therapy might be significantly less than with MTD-based chemotherapy.[15-16]As metronomic therapy reduces the level of toxicity, it lessens or even removes the need for growth-factor support to accelerate recovery from myelosuppression. Moreover, despite lower cumulative doses of drug administration, the antitumour effects of this approach, in terms of prolonging survival times, might actually be superior to conventional MTD regimens
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Chemotherapeutics do not specifically target tumour cells, but rather interfere with cell division, such as by inhibiting enzymes involved DNA replication or metabolism (for example, topoisomerases and thymidylate synthase), or microtubules. These drugs therefore also damage the normal dividing cells of rapidly regenerating tissues, such as those of the bone marrow and gut mucosa, and hair-follicle cells. Host toxicity is therefore often only marginally less than antitumour efficacy, so creating a narrow therapeutic index.
But perhaps there is a silver lining in this otherwise dark cloud, in that dividing endothelial cells are present in the growing blood vessels that are found in tumours[27] and, like other normal dividing cells, should be susceptible to chemotherapeutics.[28] Elimination of these dividing endothelial cells, or inhibition of their division, would presumably lead to an anti-angiogenic effect. Moreover, as host vascular endothelial cells are assumed to be genetically stable and lack the diverse genetic defects characteristic of cancer cells that lead to drug resistance, the putative effects of chemotherapy might be more durable in the face of continued therapy. By way of example, successive cycles of MTD-based chemotherapy can cause myelosuppression each time, the extent of which does not change appreciably.[28] If normal bone-marrow-cell progenitors acquired resistance to chemotherapy in the same way that genetically unstable, highly mutable cancer cells do, myelosuppression would gradually decline and disappear. So, the cancer cells that are resistant to a particular chemotherapeutic agent might indirectly respond to that same drug through a 'side effect' — loss of or damage to its associated vasculature, as first proposed in 1991 (REF. 29). Literature dating back to the mid-1980s shows that virtually every class of chemotherapeutic has anti-angiogenic effects or antivascular effects in various in vitro and in vivo assays.[23]
Many tumours, however, are intrinsically drug resistant or rapidly acquire resistance after showing initial responsiveness to chemotherapy regimens. So it would of dividing endothelial cells in tumour-associated blood vessels is simply too low for chemotherapy to have a significant therapeutic impact. Alternatively, the endothelial cells might be protected from chemotherapy-induced cell death by high local concentrations of endothelial-cell survival factors such as VEGF, basic fibroblast growth factor (bFGF) and angiopoietin 1 (REFS 30,31). A third explanation, uncovered in a pioneering study from Judah Folkman's laboratory,[22] is that the anti-angiogenic effects of chemotherapy are both masked and marginalized by the way chemotherapy is usually administered. In this case, the long breaks between drug administration that are necessary to allow the patient to recover from the harmful side effects of the MTD chemotherapy, especially from myelosuppression, reduce the anti-angiogenic effects of the drugs.
Timothy Browder and colleagues evaluated the anti-angiogenic and antitumour effects of the alkylating agent cyclophosphamide in immune-competent syngeneic mice that had been injected subcutaneously with various tumour types.[22] They found that this drug, when administered at the MTD, caused apoptosis of endothelial cells in the newly formed tumour microvessels.[22] A detailed temporal analysis showed that the endothelial cells were the first in the tumour to undergo apoptosis.[22]This anti-angiogenic effect did not, however, translate into a significant therapeutic benefit, apparently because the damage to the vasculature of the tumour was largely repaired during the long (2-3-week) rest/recovery periods between successive cycles of MTD-based therapy.
It was therefore proposed that if cyclophosphamide was given more frequently (FIG. 1), such as once or more per week with no extended breaks, there would be significantly less opportunity for repair of the damaged endothelium and the anti-angiogenic effects of the chemotherapy would irreversibly accumulate. This, of course, necessitates lowering the dose of the drug administered with each injection. Browder et al. showed that this more frequent, regular, lower-dose therapy, which was administered at one-third of the MTD, had impressive anti-angiogenic and antitumour effects when tested on several mouse tumour cell lines grown subcutaneously in syngeneic mice.[22] This approach allowed even very large established subcutaneous tumours, previously selected in vivo for acquired cyclophosphamide resistance using a conventional MTD regimen, to respond to the same drug and almost completely regress. In short, a state of acquired drug resistance could be reversed simply by apparently shifting the focus of the treatment away from the drug-resistant cancer-cell population to the drug-sensitive tumour endothelium.[3,22]
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preclinical results actually have many intriguing clinical precedents.[4,36] For example, 40% of patients with non-small-cell lung cancer (NSCLC) who showed no response to standard doses of intravenous etoposide administered intermittently did respond — that is, their tumours shrank by 50% of more in volume — to the same drug when it was given orally at a much lower dose using a much more frequent basis (every day or every other day), with only a 1-week break every month.[37] Similar results have been shown in patients who have been given other drugs, such as microtubule-inhibiting taxanes, for treatment of advanced metastatic breast or ovarian cancer. In these patients, weekly regimens of drug administration are being increasingly adopted, often using only 30-40% of the MTD given once every 3 weeks.[38] In women who had stopped responding to the MTD of paclitaxel or docetaxel given once every 3 weeks, tumours were found to respond in a high proportion of cases to a regimen of approximately 30-40% the MTD once every week.[13,36,38-40] However, for the most part, these are not standard-of-care regimens and their benefits remain to be validated in randomized prospective Phase III clinical trials.
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...if endothelial cells are continuously exposed to a low concentration of drug such as paclitaxel over a 6 day period (replicating metronomic therapy), endothelial cells, but not dermal fibroblasts or tumour cells, undergo apoptosis within about 5 days.[78] This delay in cytotoxicity indicates that the pro-apoptotic effects of low-dose metronomic chemotherapy on endothelial cells might not be direct, but could instead be a secondary result of some other process that is specific to the vascular endothelial cell.
There are two routes by which metronomic chemotherapy could lead to growth arrest or apoptosis of endothelial cells in the tumour neovasculature. A 'direct' pathway (left) assumes that activated, differentiated endothelial cells are intrinsically sensitive to low-dose chemotherapy, for which there is some evidence;[80-85] the same might be true for circulating endothelial progenitor cells.[17]The 'indirect' pathway (right) assumes that the levels of metronomically administered drugs are too low to induce growth arrest or apoptosis of endothelial cells. Instead, an endogenous inhibitor of angiogenesis, such as thrombospondin 1, is induced in certain cells by low-dose chemotherapy. This inhibits tumour angiogenesis and vasculogenesis, leading to a reduction in tumour neovascularization in the absence of side effects such as myelosuppression, hair loss, and nausea or vomiting.
http://www.cancerprotocol.com/low_do...motherapy.html When cancer becomes completely chemo resistant and high dose chemotherapy is no longer a viable option, is there anything left for patients and their doctors to try? Drs. Timothy Browder, Robert Kerbel, and Judah Folkman think there is... Sequential Low-Dose Chemotherapy.
The idea that chemotherapy given at lower doses may be effective where higher doses have failed at first seems implausible. The explanation offered is that the low-dose treatments do not target the tumor cells directly but the capillaries that nourish them. "In de-emphasizing the tumor cell as a target, this strategy requires a fundamental change in our approach to therapy," observes the University of California's Douglas Hanahan, A major benefit from using lower doses is that patients report fewer or no side affects. In reporting on trials run at the European Institute of Oncology, Dr. Aron Goldhersch agreed. "We see very little toxicity on white blood cells. We don't see serious nausea. We don't see vomiting." In most low-dose studies conducted up to now, even when tumors have disappeared completely, they eventually return and patients die. The explanation for the improved results appear to lie in Folkman's discovery that it is necessary to add other antiangiogenic drugs to the regimen.
"If you're a clinician and you want to do something," Kerbel said "you've got three choices: interferon, thalidomide, and the COX-2 inhibitors."
An example of a sequential low-dose regimen:
Antiangiogenic Drugs
Interferon alpha 1 million units daily
Thalidomide 50 mg daily, 1/2 hour before bedtime.
Celebrex 200mg, twice daily
In addition to the above, on a rotating basis:
Weeks 1-3 cytoxan 400mg/m2 once a week
Weeks 4-6 taxol 80-90mg/m2 once a week
Weeks 7-9 VP16 50 mg daily
Anecdotal clinical experience and laboratory studies in animal models suggests that changing chemotherapy agents every 2-3 weeks may be most effective in attacking tumors' blood supply. Recent anecdotal clinical experiences with drug resistant tumors have shown stabilization using Cytoxan 400mg/M2 weekly for 3 weeks, followed by taxol 80-90mg/M2 weekly for 3 weeks, followed by oral etoposide 50mg. orally daily for 3 weeks (or dose adjusting to titrate the WBC to between 2,000 and 3,000.) then repeating the cycle. If tumor sensitivities are known or likely, based on tumor type, it would make sense to use these agents sequentially which also may share tumor cell cytotoxicity for 3 weeks each, then repeating the cycle. (Note: etoposide is the only of these agents used more often than every 6-7 days).
When anti-angiogenic chemotherapy is applied in patients who have already depleted copper levels below the angiogenic threshold, but have not yet achieved tumor stabilization, their bone marrow shows greater sensitivity to these chemotherapeutic agents. In such situations it is best to use the above doses of these agents as total dose, rather than as a per meter squared dose, and check the CBC prior to each repeat dose of chemotherapy. Copper depleted patients will not likely tolerate etoposide (oral or IV) more often than every 6 days. If red cell growth factor support is needed, give Procrit 40,000 units the day after chemotherapy on a weekly basis. If WBC support is needed, give GMCSF (Leukine) 500 mcg. daily starting the day after chemotherapy and stopping 48 hrs. before the next dose of chemotherapy (i.e. for 3 or 4 days between doses, depending if the interval between chemotherapy doses is 6 or 7 days. Chemotherapy doses should also be attenuated as needed to maintain blood counts. If cytopenias are severe, it is better to give a very small dose of chemotherapy followed by growth factor support, than to skip doses, as endothelial cell damage from chemotherapy agents repairs very quickly. The regimen should be given continuously without stop. Sequential low-dose chemotherapy is directed at inhibiting new capillary growth. Slight tumor growth may occur during the first few weeks (supported by the existing capillary bed). Tumor shrinkage should occur ONLY as the existing capillaries break and are not replaced.
Breast. 2005 Dec;14(6):466-79. Epub 2005 Sep 30. Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy.
Munoz R, Shaked Y, Bertolini F, Emmenegger U, Man S, Kerbel RS.
Sunnybrook & Women's College Health Sciences Centre, S-217, 2075 Bayview Avenue, Toronto, Ont. Canada, M4N 3M5.
We have been studying the molecular and cellular basis of chronic low-dose, frequently administered, metronomic chemotherapy regimens for the treatment of cancer in a variety of preclinical models, including human breast cancer xenografts. The advantages of metronomic-maintenance-type chemotherapy regimens include significantly reduced host toxicity, potentially reduced costs, increased convenience for patients when oral chemotherapy drugs are used, and the possibility of adopting chronic combination therapies involving conventional chemotherapy drugs and cytostatic molecularly targeted therapies. However, a disadvantage is the empiricism associated with determining the optimal biologic dose (OBD). Recently, we have developed a surrogate biomarker approach involving measurement of circulating endothelial progenitor cells (CEPs) in peripheral blood to help determine the OBD of anti-angiogenic drugs or treatments, including metronomic chemotherapy. Using this approach we determined the OBD for different metronomic chemotherapy regimens and then tested the effect of such drugs for the treatment of established, advanced (high volume) and widespread human breast cancer metastases in immunodeficient mice. This treatment strategy, which was maintained for over 6 months, with no breaks, resulted in marked prolongation of survival and was devoid of overt toxicity. These results suggest the possibility of using metronomic chemotherapy regimens as an adjuvant therapy for early-stage disease, including breast cancer, as was demonstrated recently using long-term daily low-dose UFT for the treatment of early-stage resected non-small cell lung cancer or UFT in combination for early stage breast cancer combined with tamoxifen.
Aparna A. Kamat1, Tae Jin Kim1,5, Charles N. Landen, Jr.1, Chunhua Lu1, Liz Y. Han1, Yvonne G. Lin1, William M. Merritt1, Premal H. Thaker1, David M. Gershenson1, Farideh Z. Bischoff4, John V. Heymach2, Robert B. Jaffe6, Robert L. Coleman1 and Anil K. Sood1,3 Departments of 1 Gynecologic Oncology, 2 Thoracic/Head and Neck Medical Oncology, and 3 Cancer Biology, The University of Texas M.D. Anderson Cancer Center; 4 Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas; 5 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cheil General Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea; and 6 Center for Reproductive Sciences, Department of Obstetrics Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California Requests for reprints: Anil K. Sood, Departments of Gynecologic Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, TX 77030. Phone: 713-745-5266; Fax: 713-792-7586; E-mail: asood@mdanderson.org
ABSTRACT
Metronomic chemotherapy is the frequent administration of lowdoses of chemotherapeutic agents targeting tumor-associatedendothelial cells. We examined the efficacy of metronomic taxanesalone and in combination with AEE788—a dual epidermalgrowth factor receptor (EGFR) and vascular endothelial growthfactor receptor (VEGFR) inhibitor—in an orthotopic mousemodel of ovarian cancer. Growth-modulating effects of metronomicand maximum tolerated dose (MTD) regimens on overall survivalwere tested.
... In vivo, metronomic docetaxel resultedin significant reduction of tumor growth in the taxane-sensitivecell lines, whereas metronomic docetaxel plus AEE788 had anadditive effect resulting in significant prolongation in survival.Combination therapy was effective even in the taxane-resistantmodel. Metronomic chemotherapy alone and combined with AEE788resulted in a decrease in the proliferative index and microvesseldensity of treated tumors, whereas combination therapy increasedthe apoptotic index (P < 0.001). In vitro, metronomic taxanescaused endothelial cell toxicity at 10- to 100-fold lower concentrationscompared with MTD dosing. Metronomic regimens inhibited mobilizationof CEPs (P < 0.05) and led to a decrease in cell-free DNAlevels (P < 0.05). Our results suggest that metronomic taxanechemotherapy with dual EGFR and VEGFR inhibition is highly efficaciousand should be considered for future clinical trials. [CancerRes 2007;67(1):281–8]
..... Determining the optimal metronomic dose for docetaxel.
Due to a paucity of data regarding the optimal in vivo metronomic dose for docetaxel, we first did dose-finding experiments. Female nude mice (n = 10 in each group) injected with HeyA8 cells i.p. were treated with either vehicle or docetaxel at doses ranging from 0.5 to 5 mg/kg i.p. thrice weekly, starting at 1 week after tumor cell injection. All metronomic doses of docetaxel were highly effective in reducing tumor growth (Fig. 1). The lowest dose of metronomic docetaxel (0.5 mg/kg) resulted in an 87% reduction in mean tumor weight compared with controls (P < 0.05). Doses lower than 0.5mg/kg were not effective (data not shown). Therefore, we selected 0.5 mg/kg docetaxel thrice weekly as the optimal metronomic dose, which was used for all subsequent experiments. Long-term therapy with metronomic docetaxel.
To determine the therapeutic efficacy of metronomic docetaxel alone and in combination with AEE788, we initiated therapy 1 week after tumor cell injection according to the following six groups (10 mice per group): (a) PBS, thrice weekly; (b) MTD docetaxel 15 mg/kg, every 2 weeks; (c) metronomic docetaxel 0.5 mg/kg thrice weekly; (d) AEE788 50 mg/kg by p.o. gavage thrice weekly; (e) MTD docetaxel plus AEE788; and ( f ) metronomic docetaxel plus AEE788. In the HeyA8 model, both MTD and metronomic docetaxel monotherapy led to a 65% and 76% reduction in tumor growth, respectively, compared with PBS treatment (P < 0.05; Fig. 2A and B). Similar results were observed with AEE788 alone. Combination therapy of MTD docetaxel with AEE788 resulted in
an 89% reduction in tumor growth compared with PBS alone(P < 0.01). However, metronomic docetaxel with AEE788 resulted in the greatest efficacy with 96% tumor growth inhibition (P < 0.001). Similar results were observed in the SKOV3ip1 model, with the greatest efficacy noted in the metronomic docetaxel plus AEE788 group (P < 0.001; Fig. 2C and D). In both experiments, there was no significant difference in the average mouse weights among the various treatment groups (data not shown).
.... To study the potential efficacy of metronomic dosing in experimental models of chemotherapy resistance, we used the taxane-resistant HeyA8-MDR cell line. As expected, there was no effect on tumor growth with MTD docetaxel in the HeyA8-MDR model. Interestingly, metronomic docetaxel monotherapy resulted in a 57% reduction of tumor growth compared with the PBS group (P < 0.05; Fig. 2E and F). Furthermore, the combination of either MTD (P < 0.01) or metronomic docetaxel (P < 0.001) with AEE788 was superior to the control arm. Effect of long-term metronomic therapy on survival in ovarian cancer.
Based on these encouraging results with regard to inhibition of in vivo tumor growth using metronomic regimens, we next examined the effects of these regimens on survival using the HeyA8 model. Treatment with MTD (P = 0.03) and metronomic docetaxel (P = 0.002) both significantly prolonged survival, whereas AEE788 alone did not have a significant effect (P = 0.09). The most significant effect on survival time was in the combination arm with metronomic docetaxel and AEE788, where survival was increased by at least 60 days (P < 0.0001; Fig. 3A). After 100 days, the remaining mice were sacrificed. Overall, the difference in survival among the various treatment arms was highly significant (log-rank test, P < 0.0001; Fig. 3A). There was no significant difference in mean body weight of the mice in the various treatment groups (data not shown), suggesting that treatment was well tolerated.
Patients with recurrent or chemorefractory disease frequently have large tumors at the initiation of therapy. To examine the efficacy of metronomic therapy in the presence of established tumors, we conducted a survival experiment with the HeyA8 model where therapy was initiated 17 days after injection (palpable tumors of 0.5–0.75 cm3). Combination therapy with metronomic docetaxel and AEE788 significantly prolonged survival even in this model (Fig. 3B; P < 0.0001).
Assessment of CECs and cell-free DNA levels.
Antiangiogenic agents have been shown to have differential effects on the levels of CECs in the circulation (22). Therefore, we sought to determine the levels of two subpopulations of CECs, namely CEP cells and mature CECs, following short-term treatment of mice with metronomic docetaxel alone and in combination with AEE788, as potential surrogate biomarkers of response. Mice (n = 8 per group) bearing HeyA8 tumors were treated (starting at day 17) for 1 week with either PBS, metronomic docetaxel alone, or in combination with AEE788; levels of CECs were assessed using flow cytometry on murine peripheral blood with a modified protocol as previously described (22). There was no significant difference in the levels of mature CECs in the various treatment groups (Fig. 5A). Treatment with AEE788 resulted in a 69% reduction in CEPs compared with controls (P = 0.06). Interestingly, the combination of AEE788 with metronomic docetaxel led to a 76% reduction in CEP levels (P = 0.03). Thus, treatment with AEE788 alone and in combination with metronomic docetaxel inhibited the mobilization of CEPs, which could, in part, contribute to their antiangiogenic effects.
...... These data show that metronomic scheduling of taxane basedchemotherapy enhances the efficacy of antivascular agents such as AEE788. These effects were seen at remarkably low cumulative doses of docetaxel compared with MTD doses and were well tolerated. The combination of metronomic chemotherapy with AEE788 significantly prolonged survival. More importantly, this combination regimen had efficacy even in models with established tumors as well as in the chemotherapy-resistant model.
The evolution toward metronomic administration of chemotherapeutic drugs is based on several factors. First, high-dose chemotherapy is not very effective and is associated with high toxicity (25). In addition, dose-dense chemotherapy, in which one or more chemotherapeutic agent is administered at more frequent intervals, has shown efficacy in randomized phase III clinical trials (7, 26, 27). Metronomic chemotherapy, a variant of dose-dense therapy, in which the cumulative dose is significantly less than MTD-based chemotherapy, has several potential advantages, including lower toxicity and adverse side effects (7, 28). More importantly, it seems that despite the lower cumulative doses administered, metronomic chemotherapy is superior to MTD-based regimens for inhibiting tumor growth in preclinical models (29, 30). Our findings show that metronomic docetaxel at one fifth the cumulative dose of MTD based regimens had significant effects on therapeutic response and survival. Clinically, weekly taxane chemotherapy has resulted in a high rate of objective responses even in chemotherapy-resistant cancers (31, 32). Our data support these findings in that metronomic paclitaxel and docetaxel monotherapy resulted in growth inhibition in the taxane-resistant model.
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An attractive application of metronomic chemotherapy is the
ability to combine these regimens with biological agents, in
particular antiangiogenic drugs. Certain chemotherapeutic agents, such as vinblastine, cyclophosphamide, and taxanes, have antiangiogenic properties at 1/10 to 1/20 the MTD in combination with an anti-VEGF-R2 antibody (5, 7, 33). Such combinations are particularly appealing because high local concentrations of VEGF in the tumor environment can promote multidrug resistance in tumor endothelium (6, 7, 34). Hurwitz et al. (12) reported that bevacizumab (humanized monoclonal antibody against VEGF) combined with standard chemotherapy regimens significantly improved survival for patients with advanced-stage metastatic colorectal carcinoma. These benefits may extend to the combination of antiangiogenic agents with metronomic regimens of cytotoxic agents. Theoretically, these combinations would have a more tolerable toxicity profile and could potentially be administered for prolonged periods. In our study, metronomic docetaxel plus AEE788 led to a substantial tumor reduction over metronomic chemotherapy alone, as well as a significant prolongation in survival of mice with established tumors. Thus, metronomic chemotherapy with dual inhibition of both VEGFR and EGFR
signaling with AEE788 targets both tumor cells and tumor associated endothelial cells and results in a profound effect on tumor growth inhibition.
Cancer. 2010 Jan 29. [Epub ahead of print] A phase 2 pilot trial of low-dose, continuous infusion, or "metronomic" paclitaxel and oral celecoxib in patients with metastatic melanoma.
Bhatt RS, Merchan J, Parker R, Wu HK, Zhang L, Seery V, Heymach JV, Atkins MB, McDermott D, Sukhatme VP.
Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
BACKGROUND:: Tumor angiogenesis has been associated with a poor prognosis in patients with metastatic melanoma (MM). Microtubule stabilizers and cyclooxygenase 2 (COX-2) inhibitors, alone and in combination, have produced inhibitory effects on endothelial cells and tumor angiogenesis. Angiogenesis, which is the growth of new blood vessels, is necessary for tumor growth and progression. Thus, the authors tested the safety and efficacy of a low dose of paclitaxel and celecoxib in patients with MM. METHODS:: Patients received paclitaxel 10 mg/m(2) for 96 hours weekly as a continuous intravenous infusion and oral celecoxib 400 mg twice daily. Systemic tumor response was assessed at 6-week intervals. Tumor measurements at the end of Cycle 1 were used as the baseline for assessment of tumor progression. Patients with unacceptable toxicity or disease progression after Cycle 2 relative to the end of Cycle 1 were taken off study. RESULTS:: Twenty patients were enrolled. Twelve of 20 patients (60%) had received >/=2 previous systemic therapies. Three patients did not receive treatment because of rapid disease progression. Treatment-related grade 3/4 toxicities were limited to catheter-related complications. One patient achieved a partial response, and 3 of 20 patients (15%) had stable disease for >6 months. The median time to progression was 57 days (95% confidence interval, 43-151 days), and the median overall survival was 212 days (95% confidence interval, 147-811 days). CONCLUSIONS:: Low-dose, continuous intravenous infusion paclitaxel and oral celecoxib produced disease stabilization in a significant proportion of heavily pretreated patients with MM. These findings support a role for metronomic therapy in patients with this disease. Cancer 2010. (c) 2010 American Cancer Society.
PMID: 20120033 [PubMed - as supplied by publisher]
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
2003
Maximum Tolerable Dose and Low-Dose Metronomic Chemotherapy Have Opposite Effects on the Mobilization and Viability of Circulating Endothelial Progenitor Cells1
PDF attached http://cancerres.aacrjournals.org/cg...ull/63/15/4342
Francesco Bertolini2, Saki Paul, Patrizia Mancuso, Silvia Monestiroli, Alberto Gobbi, Yuval Shaked and Robert S. Kerbel Division of Hematology-Oncology, Department of Medicine [F. B., S. P., P. M.] and Department of Experimental Oncology, IFOM-Fondazione Italiana per la Ricerca sul Cancro Institute of Molecular Oncology [S. M., A. G.], European Institute of Oncology, 20141 Milan, Italy; Molecular and Cell Biology Research, Sunnybrook and Women’s College Health Sciences Centre, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M4N 3M5 Canada [Y. S., R. S. K.]
There is growing evidence that vasculogenesis (progenitor cell-derivedgeneration of new blood vessels) is required for the growthof some neoplastic diseases. Here we show that the administrationof cyclophosphamide (CTX) at the maximum tolerable dose with21-day breaks or at more frequent low-dose (metronomic) scheduleshave opposite effects on the mobilization and viability of circulatingendothelial progenitors (CEPs) in immunodeficient mice bearinghuman lymphoma cells. Animals treated with the maximum tolerabledose CTX experienced a robust CEP mobilization a few days afterthe end of a cycle of drug administration, and tumors rapidlybecame drug resistant. Conversely, the administration of metronomic CTX was associated with a consistent decrease in CEP numbersand viability and with more durable inhibition of tumor growth.Our findings suggest that metronomic low-dose chemotherapy regimensare particularly promising for avoiding CEP mobilization and,hence, to potentially reduce vasculogenesis-dependent mechanismsof tumor growth.
Med Oncol. 2009 Apr 14. [Epub ahead of print] Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy.
Nelius T, Klatte T, de Riese W, Haynes A, Filleur S.
Department of Urology, Texas Tech University Health Sciences Center, 3601 4th Street, Stop 7260, Lubbock, TX, 79430-7260, USA, thomas.nelius@ttuhsc.edu.
For patients with docetaxel-resistant hormone-refractory prostate cancer (HRPC) no standard chemotherapeutic treatment exists. In this study, we evaluate the efficacy of cyclophosphamide (CP)-based metronomic chemotherapy in this patient population. Patients with metastatic HRPC with disease progression under docetaxel-based chemotherapy were eligible. The primary endpoint was prostate-specific antigen (PSA) response. Secondary endpoints were survival and toxicity. Low-dose CP (50 mg/d) and dexamethasone (1 mg/d) were administered orally in a metronomic manner. Treatment was continued until disease progression or intolerable side effects occurred. Seventeen patients were enrolled in this study. The median follow-up was 12 weeks (range: 4-60). Median age was 68 years (range: 42-85). Median PSA at study entry was 134 ng/ml (range: 46.0-6554). Nine patients had a PSA response (median 44.4%), four patients >/=50% and five patients <50%. Eight patients had a PSA progression. Overall survival was 24 months. Five patients reported a decrease in bone pain after 4 weeks' treatment. No grade 3 and 4 toxicities were noted. In this study, low-dose metronomically administered CP demonstrated efficacy as a second-line treatment in patients with docetaxel-resistant HRPC. The treatment was well tolerated and almost without toxicity. Further advantages of low-dose CP were its convenient oral administration, dosing schedule, low cost, and low-toxicity profile. These attributes in combination with immunoregulatory and antiangiogenic potentials make CP also a prime candidate for combination with other treatment regimens.
PMID: 19365737 [PubMed - as supplied by publisher]
Eur J Gynaecol Oncol. 2009;30(4):449-51. Prolonged clinical benefit from platinum-based chemotherapy in a patient with metastatic triple negative breast cancer.
Krockenberger M, Engel JB, Häusler S, Dietl J, Honig A.
Department for Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany.
Triple negative breast cancer is a recently defined subgroup of tumors which do not express receptors for estrogen or progesterone and which do not show any overexpression of HER2 receptors. Tumors with these histopathologic features have an unfavorable prognosis and at present there is no standard chemotherapy regimen available. However, experimental studies and very recently some clinical data showed a benefit from platinum-based chemotherapy. We treated a 52-year-old caucasian female with metastatic triple negative breast cancer. She suffered from extensive liver disease resistant to taxane treatment and yttrium radiotherapy. Cisplatin/ifosfamide (12 cycles) induced regression of the liver metastasis from over 30 cm to 6 cm as revealed by CT scan. Dose-limiting toxicity was impairment of renal function and pancytopenia. The patient has now been stable for over ten months on a metronomic regimen of oral cyclophosphamide. This case report adds to recent evidence suggesting good clinical benefits of platinum-based regimens in early and advanced triple negative breast cancers.
PMID: 19761144 [PubMed - in process]
BMC Cancer. 2006 Sep 15;6:225. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer.
Orlando L, Cardillo A, Ghisini R, Rocca A, Balduzzi A, Torrisi R, Peruzzotti G, Goldhirsch A, Pietri E, Colleoni M.
Unit of Research in Medical Senology, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. laura.orlando@ieo.it
BACKGROUND: HER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC). METHODS: Between April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks) in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week) and CTX (50 mg daily) (CM). RESULTS: The 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts), and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts), liver (14 pts), bone (12 pts), lymph nodes (8 pts), central nervous system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5-40%), 10 stable disease (SD) (46%, 95% CI 24-68%), and 8 PD (36%, CI 17-59%). The clinical benefit (RP plus RC plus SD for > or = 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24-68%) and 27% (95% CI, 6-61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade > or =2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively. CONCLUSION: The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.
PMID: 16978400 [PubMed - indexed for MEDLINE]
Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):904-16. Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts.
du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, Hicklin DJ, Emmenegger U, Kerbel RS.
Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada.
PURPOSE: Acquired resistance to trastuzumab (Herceptin) is common in patients whose breast cancers show an initial response to the drug. The basis of this acquired resistance is unknown, hampering strategies to delay or treat such acquired resistance, due in part to the relative lack of appropriate in vivo tumorigenic models. EXPERIMENTAL DESIGN: We derived an erbB-2-positive variant called 231-H2N, obtained by gene transfection from the highly tumorigenic erbB-2/HER2-negative human breast cancer cell line, MDA-MB-231. Unlike MDA-MB-231, the 231-H2N variants was sensitive to trastuzumab both in vitro and especially in vivo, thus allowing selection of variant resistant to drug treatment in the latter situation after showing an initial response. RESULTS: The growth of established orthotopic tumors in severe combined immunodeficient mice was blocked for 1 month by trastuzumab, after which rapid growth resumed. These relapsing tumors were found to maintain resistance to trastuzumab, both in vitro and in vivo. We evaluated various therapeutic strategies for two purposes: (a) to delay such tumor relapses or (b) to treat acquired trastuzumab resistance once it has occurred. With respect to the former, a daily oral low-dose metronomic cyclophosphamide regimen was found to be particularly effective. With respect to the latter, an anti-epidermal growth factor receptor antibody (cetuximab) was effective as was the anti-vascular endothelial growth factor (anti-VEGF) antibody bevacizumab, which was likely related to elevated levels of VEGF detected in trastuzumab-resistant tumors. CONCLUSIONS: Our results provide a possible additional rationale for combined biological therapy using drugs that target both erbB-2/HER2 and VEGF and also suggest the potential value of combining less toxic metronomic chemotherapy regimens not only with targeted antiangiogenic agents but also with other types of drug such as trastuzumab.
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
Crit Rev Oncol Hematol. 2009 Aug 1. [Epub ahead of print] Weekly paclitaxel versus weekly docetaxel in elderly or frail patients with metastatic breast carcinoma: A randomized phase-II study of the Belgian Society of Medical Oncology.
Beuselinck B, Wildiers H, Wynendaele W, Dirix L, Kains JP, Paridaens R.
University Hospitals Leuven, Catholic University Leuven, Medical Oncology Department, Belgium.
This randomized phase-II trial investigated the efficacy and tolerability of weekly docetaxel or paclitaxel in metastatic breast cancer (MBC) patients considered unfit for a 3-weekly therapy. The primary study endpoint was antitumor activity, the second endpoint was tolerability, time to progression (TTP) and overall survival (OS). In intent-to-treat analysis, we observed for paclitaxel and docetaxel respectively partial response (PR) in 48% versus 38%, stable disease (SD) in 24% versus 16%, PD in 15% versus 30%. Median TTP was 21.1 weeks versus 12.7 weeks and median OS 55.7 weeks versus 32 weeks. Toxicity profiles were acceptable with more anemia and neurotoxicity for paclitaxel and more edema and fatigue for docetaxel. In patients with MBC unfit for 3-weekly docetaxel or paclitaxel, weekly administration of either compound may certainly be considered. They display different, but acceptable toxicity profiles, with levels of antitumoral efficacy comparable to those previously reported for 3-weekly regimens.
PMID: 19651523 [PubMed - as supplied by publisher]
???Weekly less effective than tri-weekly???:
Anticancer Res. 2008 Nov-Dec;28(6B):3993-5. Docetaxel for metastatic breast cancer: two consecutive phase II trials.
Campora E, Colloca G, Ratti R, Addamo G, Coccorullo Z, Venturino A, Guarneri D.
Division of Medical Oncology, "G. Borea" Hospital, Sanremo, Imperia, Italy. e.campora@as11.liguria.it
BACKGROUND: Docetaxel is the most active agent for metastatic breast cancer, but the optimal treatment regimen as a single agent has yet to be defined. PATIENTS AND METHODS: Two consecutive monocentric phase II trials of docetaxel in metastatic breast cancer were carried out. In Trial I, 36 patients received docetaxel 35 mg/m2 weekly for 6 weeks every 8 weeks and in Trial II, 29 patients received docetaxel 100 mg/m2 day 1 every 21 days. RESULTS: Patient characteristics were comparable. However, patients with liver involvement comprised 25% of cases in Trial I and 55% in Trial II. The overall response rate on an intention-to-treat basis was 19% vs. 45% in Trial I and II respectively; time to progression was 3.8 vs. 7.5 months respectively, and overall median survival was comparable in each trial. CONCLUSION: Docetaxel given at 100 mg/m2 every three weeks appears to be a safe, effective regimen that can be applied in common clinical practice for the treatment of metastatic breast cancer.
PMID: 19192662 [PubMed - indexed for MEDLINE]
Oncology. 2009;77(3-4):212-6. Epub 2009 Sep 4. Weekly docetaxel with or without gemcitabine as second-line chemotherapy in paclitaxel-pretreated patients with metastatic breast cancer: a randomized phase II study conducted by the Hellenic Co-Operative Oncology Group.
Papadimitriou CA, Kalofonos H, Zagouri F, Papakostas P, Bozas G, Makatsoris T, Dimopoulos MA, Fountzilas G.
Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece.
OBJECTIVE: A randomized phase II trial was conducted to test whether the addition of gemcitabine to weekly docetaxel could improve the objective response rate and survival outcomes as second-line chemotherapy in patients with metastatic breast cancer who have failed a paclitaxel-containing regimen. METHODS: Patients were randomized to receive either weekly docetaxel 40 mg/m(2) (group A, n = 34) or the combination of weekly docetaxel 35 mg/m(2) with gemcitabine 600 mg/m(2) (group B, n = 41). Three consecutive weekly infusions followed by a 1-week rest period represented 1 chemotherapy cycle. RESULTS: The objective response rate was 18% and 27.5% in group A and B, respectively (p = 0.413). No statistically significant differences were demonstrated in terms of median overall survival and time to disease progression. The rate and grade 3 and 4 neutropenia were higher in group B (23 vs. 3%). CONCLUSIONS: The weekly administration of docetaxel and gemcitabine did not result in superior clinical outcomes over weekly docetaxel. Copyright 2009 S. Karger AG, Basel.
Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles
Sharon L. Sanborn1, Matthew M. Cooney1 , Afshin Dowlati1, Joanna M. Brell1, Smitha Krishnamurthi1, Joseph Gibbons1, Joseph A. Bokar1, Charles Nock1, Anne Ness1 and Scot C. Remick2
(1)
Division of Hematology and Oncology, University Hospitals Case Medical Center, Case Comprehensive Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, OH 44106, USA
(2)
Mary Babb Randolph Cancer Center, West Virginia University, 1801 Health Sciences South, P.O. Box 9300, Morgantown, WV 26506, USA
Received: 25 February 2008 Accepted: 8 April 2008 Published online: 10 May 2008
Summary Purpose: Pre-clinical models have demonstrated the benefit of metronomic schedules of cytotoxic chemotherapy combined with anti-angiogenic compounds. This trial was undertaken to determine the toxicity of a low dose regimen using docetaxel and thalidomide. Patients and Methods: Patients with advanced solid tumors were enrolled. Thalidomide 100mg twice daily was given with escalating doses of docetaxel from 10 to 30mg/m2/week. One cycle consisted of 12 consecutive weeks of therapy. The maximal tolerated dose (MTD) was defined as the dose of thalidomide along with docetaxel that caused ≤grade 1 non-hematologic or ≤grade 2 hematologic toxicity for cycle one. Results: Twenty-six patients were enrolled. Dose-limiting toxicities (DLTs) were bradycardia, fatigue, fever, hyperbilirubinemia, leukopenia, myocardial infarction, and neutropenia. Prolonged freedom from disease progression was observed in 44.4% of the evaluable patients. Conclusions: This anti-angiogenic regimen was well tolerated and demonstrated clinical benefit. The recommended phase II dosing schedule is thalidomide 100mg twice daily with docetaxel 25mg/m2/week.
Keywords Metronomic - Docetaxel - Thalidomide - Angiogenesis - Phase I
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
Metronomic Schedule of Paclitaxel Is Effective in Hormone Receptor–Positive and Hormone Receptor–Negative Breast Cancer
Rita S. Mehta, Donna Jackson, Toni Schubbert Department of Medicine, Division of Hematology and Oncology, University of California Irvine, Irvine, CA To the Editor:
Hugh et al1 are to be lauded for their comprehensive analysisof the benefit estimation of a docetaxel-based regimen comparedwith the standard fluorouracil-based regimen in various breastcancer subsets. After comparing trials in which paclitaxel ratherthan docetaxel was used, they suggest that the benefit seenwith docetaxel in hormone receptor–positive subsets mayhave resulted from either docetaxel being a more efficacioustaxane, or a docetaxel-specific schedule that was better thanthe schedule of paclitaxel once every 3 weeks. However, theydo not expand on paclitaxel scheduling; we believe this is acrucial omission in their discussion. In fact, missing fromtheir discussion is a major phase III randomized trial thatclearly established the superiority of paclitaxel once per weekover paclitaxel once every 3 weeks,2 whereas the overall survivalbenefit of docetaxel once every 3 weeks over paclitaxel onceevery 3 weeks has yet to be demonstrated. In fact, the superiorityof paclitaxel once per week over paclitaxel once every 3 weekswas first predicted by Green et al,3 who showed paclitaxel onceper week compared with paclitaxel once every 3 weeks increasedpathologic complete response—a surrogate of disease-freeand overall survival—in the neoadjuvant setting in operablebreast cancer, in both hormone receptor–positive and hormonereceptor–negative subsets. In the confirmatory trial bySparano et al,2 which evaluated the 5-year disease-free andoverall survival end points and compared the two taxanes andthe two taxane schedules in a 2 x 2 factorial design, paclitaxelonce per week compared with paclitaxel once every 3 weeks significantlyimproved 5-year progression-free survival in hormone receptor–negativebreast cancer, including triple-negative and human epidermalgrowth factor receptor 2 (HER2) –positive subsets of breastcancer, and hormone receptor–positive breast cancer, whichcombines luminal-A and luminal-B subtypes of breast cancer.This was seen despite the fact that patients with HER2-positivebreast cancer (including luminal-B breast cancer, an HER2-positivesubtype) were preferentially enrolled onto the alternate trastuzumabtrials; these patients were more likely to have chemotherapy-sensitivedisease and therefore more likely to benefit from weekly paclitaxel.It is likely that the small subgroup of patients with hormonereceptor–positive breast cancer with low Ki-67 proliferationindex that did not benefit from a docetaxel-based regimen inthe study by Hugh et al1 may not have benefited from paclitaxelonce per week either. This subgroup may be akin to the groupidentified by multigene assay that did not benefit from first-generationchemotherapy regimens. Until this subset of patients who willnot benefit from paclitaxel once per week is identified, weeklypaclitaxel after anthracyclines should be standard in all subsetsof breast cancer, including triple-negative, hormone receptor–positive(estrogen receptor–positive and/or progesterone receptor–positiveand either HER2-positive and/or Ki67high breast cancer), HER2–positive,and luminal-A (estrogen receptor–positive and/or progesteronereceptor–positive but not HER2-positive or Ki67high breastcancer)2–7 breast cancer. Moreover, drug-specific optimalschedules of chemotherapy must always be compared when comparingacross trials and/or assessing outcome in different subsetsof breast cancer, because optimal schedules of various chemotherapiesare an important advancement in the treatment of various malignancies,demonstrated convincingly in Ewing's sarcoma and ovarian cancer,8,9in addition to breast cancer.
Authors' Affiliations:1Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; 2Clinical Pharmacology Research Core, Medical Oncology Clinical Research Unit, National Cancer Institute, NIH, Bethesda, Maryland; and 3Abraxis BioScience, Santa Monica, California
Requests for reprints:
Robert S. Kerbel, Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Room S-217, 2075 Bayview Avenue, Toronto, Ontario, Canada, M4N 3M5. Phone: 416-480-5711; Fax: 416-480-5884; E-mail: Robert.Kerbel@sri.utoronto.ca.
Purpose: Low-dose metronomic chemotherapy treatments, especially when combined with ‘dedicated’ antiangiogenic agents, can induce significant antitumor activity without serious toxicity in various preclinical models. It remains unclear, however, whether some cytotoxic drugs are better suited for metronomic regimens than others. Paclitaxel appears to be a strong candidate for metronomic chemotherapy given its ability to inhibit endothelial cell functions relevant to angiogenesis in vitro at extraordinarily low concentrations and broad-spectrum antitumor activity. Clinically relevant concentrations of the formulation vehicle cremophor EL in Taxol, however, were previously reported to nullify the antiangiogenic effect of paclitaxel, the result of which would hamper its usefulness in metronomic regimens. We hypothesized that ABI-007, a cremophor EL–free, albumin-bound, 130-nm form of paclitaxel, could potentially alleviate this problem.
Experimental Design: The antiangiogenic activity of ABI-007 was assessed by multiple in vitro assays. The in vivo optimal dose of ABI-007 for metronomic chemotherapy was determined by measuring circulating endothelial progenitors in peripheral blood. The antitumor effects of metronomic and maximum tolerated dose ABI-007 and Taxol were then evaluated and compared in severe combined immunodeficient mice bearing human MDA-MD-231 breast cancer and PC3 prostate cancer xenografts. Results: ABI-007 significantly inhibited rat aortic microvessel outgrowth, human endothelial cell proliferation, and tube formation. The optimal metronomic dose of ABI-007 was determined to be between 3 and 10 mg/kg. Metronomic ABI-007 but not Taxol, significantly suppressed tumor growth in both xenograft models. Furthermore, the antitumor effect of minimally toxic metronomic ABI-007 approximated that of the maximum tolerated dose of Taxol. Conclusions: Our results underscore the influence of formulation vehicles on the selection of cytotoxic drugs for metronomic chemotherapy.
An alternative dosing regimen to pulsatile maximum tolerated dose (MTD) or “dose dense” and dose-intensive chemotherapy is “metronomic chemotherapy”: the frequent administration of such drugs at close regular intervals with no prolonged breaks over long periods of time (1). The reduced toxicity and comparable or even increased efficacy of metronomic regimens compared with some MTD counterparts have been shown in a number of preclinical models (2, 3). In addition, metronomic chemotherapy regimens are particularly well suited for long-term combination with relatively non–toxic-targeted biological therapeutics especially antiangiogenic drugs (4, 5), sometimes being used after an initial short course of MTD chemotherapy (i.e., “chemo-switching” protocols; refs. 4, 6). Some phase II clinical trials have been reported with encouraging results, both in terms of antitumor efficacy and reduced toxicity, although such results need to be validated in larger randomized phase II or III trials (7–9). These trials have involved combinations of two metronomically given drugs [e.g., cyclophosphamide and methotrexate (7) or cyclophosphamide and etoposide (8)] given orally on a daily basis, or similar protocols in combination with a drug such as bevacizumab (Avastin), the anti-vascular endothelial growth factor antibody (9).
Virtually every class of chemotherapeutic drug has been reported to have antiangiogenic properties (10), which in many cases can be amplified by metronomic dosing schedules (1). However, the selection of chemotherapeutic drugs for metronomic regimens remains somewhat arbitrary. It is not clear whether some agents or classes of agents are better suited for metronomic chemotherapy than others. Taxanes, such as paclitaxel, would seem to be excellent candidates based on the finding that ultra low (e.g., picomolar) concentrations of paclitaxel can selectively inhibit endothelial functions relevant to angiogenesis, or even kill such cells (11–15). In addition, long-term metronomic chemotherapy using microtubule-inhibiting taxanes as opposed to mutagenic and hence potentially carcinogenic DNA damaging drugs, such as alkylating agents, could also be an advantage, especially in patients receiving adjuvant metronomic therapy regimens over long periods of time for early-stage disease (16). Furthermore, taxane metronomic chemotherapy may be useful to combine with metronomic chemotherapy using another class of drug, such as anti-metabolites (e.g., UFT, the oral 5-fluorouracil prodrug; ref. 16). For example, we have recently reported that a concurrent combination of daily oral low-dose UFT and cyclophosphamide can successfully control highly advanced visceral metastases of human breast cancer in immunodeficient mice, whereas UFT or cyclophosphamide used alone could not (17). However, clinically relevant concentrations of the formulation vehicle cremophor EL in Taxol were previously reported to nullify the antiangiogenic activity of paclitaxel, suggesting that this agent or other anticancer drugs formulated in cremophor EL and other commonly used solubilization vehicles, such as polysorbate 80 (Tween 80), may need to be used at much higher doses than anticipated to achieve effective metronomic chemotherapy (18). As such, the advantage of reduced acute serious side effects associated with low-dose paclitaxel regimens versus conventional MTD paclitaxel may be compromised. Clearly, the presence of cremophor EL in Taxol hampers the use of paclitaxel in metronomic chemotherapy. This may explain, for example, the results of Klement et al. (19), in which metronomic Taxol on its own had little obvious effects on transplanted primary human breast tumors in several models.
ABI-007 (Abraxane), a novel cremophor EL–free, albumin-bound, 130-nm form of paclitaxel, was developed to retain the therapeutic benefits of paclitaxel but eliminate cremophor EL–associated toxicities in the Taxol formulation. Several clinical trials have shown the improved pharmacokinetic and toxicity profiles as well as therapeutic efficacy of ABI-007 over Taxol in MTD regimens (20–24). We hypothesized that the cremophor EL–free nature of ABI-007 may render paclitaxel-based metronomic chemotherapy feasible. With this in mind, the primary objective of this study was to evaluate the therapeutic potential of paclitaxel-based metronomic regimens using ABI-007.
Discussion
Our results show that metronomic chemotherapy using albumin-bound nanoparticle paclitaxel (ABI-007), but not paclitaxel formulated in cremophor EL (Taxol), exhibits potent in vivo antitumor activity. It was previously reported that clinically relevant concentrations of formulation vehicles, such as cremophor EL, nullify the in vitro antiangiogenic effect of taxanes (18). Paclitaxel at 4 nmol/L dissolved in DMSO but not in cremophor EL suppressed rat aortic angiogenesis and HUVEC proliferation (18). In the present study, ABI-007 at 5 nmol/L induced responses similar to those elicited by paclitaxel at 4 nmol/L dissolved in DMSO, indicating that the antiangiogenic property of paclitaxel was effectively delivered by cremophor EL–free ABI-007. Desai et al. (32) recently showed that paclitaxel in ABI-007 is actively transported into and across endothelial cells by gp60 (a specific albumin receptor)–mediated caveolar transcytosis, a process that is inhibited by cremophor EL in Taxol.
One cycle of either MTD ABI-007 or MTD Taxol was shown herein to cause marked tumor growth inhibition and transient regression in two different xenograft models (MDA-MB-231 and PC3). However, MTD Taxol–treated tumors rapidly resumed growth 3 weeks after the last dose of drug (day 42), whereas the growth of MTD ABI-007–treated tumors continued to be suppressed. The ability of MTD ABI-007 but not MTD Taxol to significantly reduce viable CEPs in MDA-MB-231 tumor-bearing mice might contribute, at least in part, to the enduring antitumor effect of the former. A higher paclitaxel plasma clearance and a larger volume of distribution for ABI-007 than for Taxol was recently reported in humans (33) as well as more rapid cellular uptake and binding (32), suggesting that paclitaxel in the ABI-007 formulation might be more effective against CEPs than Taxol. Higher intratumoral paclitaxel concentration achieved by the ABI-007 formulation could be another contributing factor (32, 33). We cannot explain why there was a lack of a significant decrease in viable CEPs by MTD ABI-007 in PC3 tumor-bearing mice. The possibility that the s.c. PC3 tumors might be less dependent on recruitment of CEPs for angiogenesis compared with the orthotopic MDA-MB-231 tumors cannot be excluded.
The significant weight loss and transient paralysis associated with MTD ABI-007 treatment and the absence of cremophor EL in the formulation prompted us to explore the feasibility of using ABI-007 in metronomic regimens as a less toxic but still highly effective antitumor alternative, one that would be well suited for long-term combination with other drugs, such as vascular endothelial growth factor–targeted antiangiogenic drugs (4, 6).
....
metronomic ABI-007 at 3 to 10 mg/kg given i.p. daily for 4 weeks effectively inhibited MDA-MB-231 and PC3 tumor growth. The observed decrease in tumor volume was accompanied by a dose-dependent reduction in viable CEP levels in both xenograft models. It should also be noted that the total dose of ABI-007 given over 4 weeks in the metronomic regimen, especially in the 10 mg/kg/d treatment group, was substantially higher than that given over 5 days in the MTD regimen (280 versus 150 mg), and yet no significant weight loss was evident in the former. In marked contrast, metronomic Taxol failed to suppress tumor growth or significantly alter viable CEP levels.
...A trend of decreasing angiogenesis with increasing metronomic ABI-007 doses was evident, whereas MTD Taxol and MTD ABI-007 did not seem to block angiogenesis, although statistical significance was not reached with any treatment. Viable CEP levels may be a more sensitive marker than intratumoral microvessel density or Matrigel plug angiogenesis in the evaluation of response to treatment modalities with an antiangiogenic/antivasculogenic component. Although the mechanistic basis of metronomic chemotherapy is thought to be primarily antiangiogenic (2–4, 30), recent evidence showed that long-term metronomic chemotherapy in mice using cyclophosphamide can also stimulate immune responses by augmenting memory T cells and depleting both regulatory and suppressor T cells (35). We cannot exclude the possibility that metronomic chemotherapy using paclitaxel may also induce similar immunomodulatory responses. It is becoming increasingly clear that metronomic chemotherapy regimens exert multiple effects in addition to angiogenesis inhibition. In summary, we have shown that paclitaxel in the absence of cremophor EL is a viable and effective drug for metronomic chemotherapy. The therapeutic potential of metronomic ABI-007 given alone or in combination with other anticancer and/or antiangiogenic agents warrants investigation in the clinical setting. Our findings especially underscore the importance of selecting an optimal formulation strategy for cytotoxic drugs (and other investigational agents) to be used in metronomic chemotherapy regimens. Clearly, the potential of the nanoparticle albumin-bound technology extends beyond paclitaxel. For instance, Nab-028, the novel taxane ABI-028 formulated as albumin-bound nanoparticles, showed improved efficacy and lower toxicity than ABI-028 formulated in Tween 80 (36). 17-(Allylamino)-17-demethoxygeldanamycin, a hydrophobic drug that inhibits HSP90 and shows poor tolerability when solubilized in a DMSO-egg lecithin vehicle, was successfully prepared as an albumin-bound nanoparticle formulation suitable for i.v. administration (37). Finally, with respect to the use of taxanes in metronomic chemotherapy regimens, a comparison of nanoparticle-based formulations, such as ABI-007, with orally bioavailable taxanes (e.g., BMS-275183) would seem timely because our results suggest that metronomic chemotherapy with low-dose, cremophor EL–free taxanes should be feasible and effective.
Metronomic Cyclophosphamide and Capecitabine Combined With Bevacizumab in Advanced Breast Cancer FULL TEXT LINK (PDF attached) Silvia Dellapasqua, Francesco Bertolini, Vincenzo Bagnardi, Elisabetta Campagnoli, Eloise Scarano, Rosalba Torrisi, Yuval Shaked, Patrizia Mancuso, Aron Goldhirsch, Andrea Rocca, Elisabetta Pietri, Marco Colleoni
From the Medical Senology Research Unit and Division of Medical Oncology, Department of Medicine; Division of Hematology-Oncology, Department of Medicine; and Division of Epidemiology and Biostatistics, European Institute of Oncology; Department of Statistics, University of Milan-Bicocca, Milan, Italy; Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and Oncology Institute of Southern Switzerland, Bellinzona and Lugano, Switzerland
Corresponding author: Marco Colleoni, MD, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; e-mail: marco.colleoni@ieo.it Purpose Metronomic chemotherapy has shown efficacy in patients withmetastatic breast cancer. When used in association with targetedantiangiogenic drugs, it was more active than metronomic therapyalone in preclinical and clinical studies. Patients and Methods Patients with advanced breast cancer were candidates to receivemetronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide(50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks). Results In 46 assessable patients, we observed one complete response(CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%)with stable disease (SD), and five patients (11%) with progressivedisease, for an overall response rate of 48% (95% CI, 33% to63%). Additional long-term disease stabilization (SD 24 weeks)occurred in eight patients, for an overall clinical benefit(CR + PR + SD 24 weeks) of 68% (95% CI, 51% to 81%). Mediantime to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicitywas generally mild. Grade 3 or 4 nonhematologic adverse effectsincluded hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting(n = 2). Higher baseline circulating endothelial cells (CECs)were correlated with overall response (P = .02), clinical benefit(P = .01), and improved progression-free survival (P = .04). Conclusion Treatment with metronomic capecitabine and cyclophosphamidein combination with bevacizumab was effective in advanced breastcancer and was minimally toxic. The number of baseline CECssignificantly correlated with response and outcome, thereforesupporting further studies on this surrogate marker for theselection of patients to be candidates for antiangiogenic treatments.
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previously showed that the probabilityof prolonged CB with metronomic therapy was higher in endocrine-responsiveMBC.23 These results might be related to the biology of endocrine-responsivedisease, which is characterized by indolent, low-proliferatingtumors and, therefore, more likely to have prolonged stabilization.27Moreover, there is a biologic rationale for improved activityof antiangiogenic treatment in endocrine-responsive tumors.28Several growth factors influence proliferation and survivalof ER-positive hormone-resistant disease.29 In particular, VEGFis elevated in patients with endocrine-responsive disease whodo not respond to hormone therapy, therefore contributing todisease progression and resistance to endocrine therapies.30-32
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We showed that baseline and viableCECs were significantly increased in patients who had a clinicalresponse and in patients who achieved a CB. Moreover, patientswho had a baseline increased apoptotic CEC count had a significantlybetter PFS. Flow cytometry viability studies indicated thatapoptotic CEC count was related to total CEC count (data notshown). Therefore, the baseline total, viable, and apoptoticCEC count might represent an indirect measure of the angiogenicturnover and an indicator of better response to antiangiogenictherapy, supporting the use of these treatments in patientsexpressing high levels of baseline CECs. Further prospectivetrials are required to confirm the value of these data in patientswho are candidates for antiangiogenic agents. If confirmed,future selection of antivascular agents should also be basedon the CEC count before treatment. In conclusion, the results of this study indicate that metronomiccapecitabine and cyclophosphamide combined with bevacizumabprovide long-term disease control in a high proportion of patients,without significant toxicity despite prolonged use. The lowburden in terms of personal costs to the patient and the possibilityof continuing the treatment for up to several months in responders,as is often required in advanced breast cancer patients, supportthis regimen as an additional therapeutic tool in MBC patients.
published online ahead of print at www.jco.org on September15, 2008.
Supported in part by Associazione Italiana per la Ricerca sulCancro, Instituto Superiore di Sanitá, and the EuropeanUnion Integrated Project "Angiotargeting."
Presented in part at the 43rd Annual Meeting of the AmericanSociety of Clinical Oncology, June 1-5, 2007, Chicago, IL.
Authors’ disclosures of potential conflicts of interestand author contributions are found at the end of this article
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
Cancer Immunol Immunother. 2007 May;56(5):641-8. Epub 2006 Sep 8. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.
Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B.
Unité INSERM 517, Faculté de Médecine, Dijon, France. francois.ghiringhelli@wanadoo.fr
CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as "metronomic" therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy.
PMID: 16960692 [PubMed - indexed for MEDLINE]
J Clin Oncol. 2008 Oct 20;26(30):4899-905. Epub 2008 Sep 15. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer.
Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, Shaked Y, Mancuso P, Goldhirsch A, Rocca A, Pietri E, Colleoni M.
Medical Senology Research Unit and Division of Medical Oncology, Department of Medicine, European Institute of Oncology, Milan, Italy.
PURPOSE: Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in preclinical and clinical studies.overall clinical benefit (CR + PR + SD > or = 24 weeks) of 68% PATIENTS AND METHODS: Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks). RESULTS: In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD > or = 24 weeks) occurred in eight patients, for an (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04). CONCLUSION: Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.
PMID: 18794539 [PubMed - indexed for MEDLINE]
Gan To Kagaku Ryoho. 2009 Sep;36(9):1525-8. [A case of stage IV breast cancer with large cancer ulcer responding to combination therapy of capecitabine and medroxyprogesterone acetate and cyclophosphamide]
[Article in Japanese] Konishi K, Hasegawa N, Kaneko H, Iimura Y, Shoji Y, Kawabata M.
Dept. of Surgery, Kushiro City General Hospital.
A 53-year-old woman suffering from nausea and vomiting was admitted to our hospital. There was a large ulcer from her left anterior chest to her right side chest. After pathological examination from the ulcer, she was diagnosed as breast cancer, scirrhous carcinoma. The estrogen and progesterone receptors were positive in the tumor. HER2 score was 1+ in the tumor. The stage was T4bNxM1(OTH). Uterine metastases of the breast cancer caused obstructive nephropathy. Ureteral obstruction was treated by urinary tract catheter. After improvement of renal failure, chemotherapy with 5-FU+epirubicin+cyclophosphamide (FEC) and docetaxel was performed. The efficacy was judged as stable disease (SD). For third-line chemotherapy, she was then treated with oral combination chemoendocrine therapy with capecitabine and medroxyprogesterone acetate. After the combination chemoendocrine therapy, the local tumor was remarkably reduced. With added cyclophosphamide, the partial response (PR) continued for 19 months. She died of peritonitis carcinomatosa and pleuritis carcinomatosa. No adverse reactions occurred with the combination chemoendocrine therapy. It is suggested that this oral combination chemoendocrine therapy may be useful with consideration for treatment effectiveness and the quality of life of the patient.
PMID: 19755825 [PubMed - indexed for MEDLINE]
LETTER TO THE EDITOR Successful treatment with low-dose capecitabine for disseminated esophageal adenocarcinoma
H. CARSTENS & M. ALBERTSSON
Department of Oncology, Karolinska University Hospital, So¨dersjukhuset, Huddinge, Stockholm, Sweden
To the Editor A 75-year-old man was diagnosed in 2004 with adenocarcinoma of the esophagus. At the time of diagnosis the disease was considered resectable and surgery was done in April 2004. Histological examination of the resected esophagus showed poorly
differentiated adenocarcinoma with growth extending through all wall layers and metastases in all 20 resected lymph nodes however radically resected.
Postoperative complications prolonged care in the intensive care unit and his clinical status was still poor (Karnofsky 60), when he came to see the oncologist 2 months after surgery. He was therefore considered too weak for adjuvant chemotherapy and
was actively monitored with regular CT scanning and clinical examinations. During the first year of follow-up his clinical condition was improved and CT scan showed no signs of cancer. About one year after surgery, in March 2005, CT scan showed liver metastases. Since his clinical status and quality of life were good, active monitoring was continued. Over the next 6 months liver metastases were slowly progressing and new changes appeared in the lungs and there were enlarged para-aortic lymph nodes. By September 2005, he became symptomatic from his metastatic tumor, with difficulties eating, back and stomach pain, coughing, and breathing problems. Palliative treatment with Oxaliplatin- 5-Fluorouracil/Leucovorin was initiated. This was administered for 2 months during which time symptoms diminished and partial regression (PR) of the tumor was seen on CT scan. However, treatment had to be interrupted due to severe nephrotoxicity arising from the combination of NSAIDs and x-ray contrast. During the following 6 months, while recovering from renal failure, no antitumor treatment was given. By June 2006 CT scan showed progressive disease in all locations and the patient suffered from pain and weight loss. At that time treatment was reinitiated with low-dose capecitabine at a continuous dose of 500 mg/day. There was a clinical response already after one month and by 2 months therapy, CT scan
showed good tumor regression and the patient’s clinical status had further improved, with weight gain, absence of pain, and good quality of life. Onassessment after 4 months, CT scan showed further regression of changes in the lungs, liver, and lymph nodes. Some metastases were no longer measurable (Figure 1).
At the time his disease had progressed in June 2006, therapeutic options were highly limited because of the patient’s age and compromised renal function, which included mild residual elevation of serum creatinine (S-creatinine 125 micro mol/l). One option would have been no treatment at all, but he wanted treatment if possible. Consequently, a relatively non-toxic treatment regimen was chosen in order to provide the best possible quality of life. To date in December 2006 his improvement has been
sustained and his quality of life remains excellent.
Continuously administered low-dose chemotherapy with metronomic scheduling seems to be clinically effective for various types of tumors and is well tolerated, as supported by a range of clinical data. Two breast cancer studies have explored this approach.
In one, low-dose oral cyclophosphamide added to Letrozole (n/57) was compared to
Letrozole alone (n/57) as primary treatment ofestrogen receptor-positive breast cancer in elderly women. Overall response was improved by 15.8% (87.7% vs. 71.9%) in the combination therapy group. There was also a significant difference in VEGF reduction [1].
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CONCLUSION: Both letrozole and letrozole plus cyclophosphamide treatmentsappeared active as PST in elderly breast cancer patients. Metronomicscheduling of cyclophosphamide may have an antiangiogeneticeffect and the combination of letrozole plus cyclophosphamidewarrants testing in a randomized phase III trial.
Conclusions
Continuously low-dose CTX and MTX is minimally toxic and effectivein heavily pretreated breast cancer patients. A drop in VEGFwas associated with the treatment and so alternative hypotheses,other than that of direct toxicity on tumor cells, must be favoredwhen trying to explain the anticancer effect.
Conclusions: This low-dose regimen consisting of daily oral cyclophosphamide and weekly vinblastine injections given concurrently with rofecoxib is associated with minimal toxicity and provides significant clinical benefit to patients with advanced solid tumors. These results are particularly encouraging given the nature of the study population, and indicate that this regimen merits further investigation in specific disease site studies.
Since the 1970s data have supported the importance of vascularization and angiogenesis for tumor growth. Several studies show that VEGF is involved in angiogenesis and is secreted in response to a variety of stress factors, thereby stimulating angiogenesis. High-dose chemotherapy has been in use for a long time. This approach requires scheduling of treatment-free intervals to allow for recovery of normal cells, e.g. hematopoietic cells. This strategy entails both a risk of drug resistance and tumour cell proliferation during treatment-free intervals. However,
this problem does not seem to be relevant in slowly proliferating vascular endothelial cells. Since angiogenesis appears to be important for tumor growth, the theory that chemotherapeutic dosing might influence tumor growth was tested. Preclinical studies support the theory that continuously administered low-dose chemotherapy may
improve the therapeutic index and be better tolerated because of less toxicity. The antitumor effect of low-dose chemotherapy seems not to result from cytotoxicity only, but rather from a mechanism involving antiangiogenesis. This has been shown by
Albertsson et al. for several cytotoxic agents [4]. Browder et al. studied the importance of chemotherapy scheduling on drug-resistant Lewis lung carcinoma
and breast cancer cell lines. With a schedule for cyclophosphamide continuously at short intervals a significant improvement in long-term suppression of tumor growth, increased apoptosis of endothelial cells, and eradication tumours were seen [5].
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Each dose of the antiangiogenic schedule of cyclophosphamideinduced the apoptosis of endothelial cells within tumors, andendothelial cell apoptosis preceded the apoptosis of drug-resistanttumor cells. This antiangiogenic effect was more pronouncedin p53-null mice in which the apoptosis of p53-null endothelialcells induced by cyclophosphamide was so vigorous that drug-resistanttumors comprising 4.5% of body weight were eradicated. Thus,by using a dosing schedule of cyclophosphamide that providedmore sustained apoptosis of endothelial cells within the vascularbed of a tumor, we show that a chemotherapeutic agent can moreeffectively control tumor growth in mice, regardless of whetherthe tumor cells are drug resistant.
Lowdose vinblastine affects functions involved in angiogenesis, such as proliferation, chemotaxis, spreading on fibronectin, and morphogenesis. Vascular proliferation
was also affected [6].
Klement et al. studied protocols for low-dose vinblastine alone and a VEGF-receptor inhibitor, alone and in combination. This treatment was tested in immunodeficient mice inoculated with human neuroblastoma cell lines. Both treatments alone produced tumor regression and inhibition of angiogenesis. However the combination therapy yielded complete and sustained tumor regression without toxicity or development of drug resistance and this effect persisted throughout the course of treatment [7]. Tomoda et al. inoculated a cell line of highly metastasing osteosarcoma, into Figure 1. (a) Liver metastases before treatment. (b) Liver metastases after 2 months therapy. (c) Liver metastases after 4 months therapy.
Successful treatment with low-dose capecitabine 867 Acta Oncol Downloaded from informahealthcare.com by 173.53.243.92 For personal use only.
rats and confirmed this finding. Low-dose methotrexate inhibited development of lung metastases and an inhibitory effect on endothelial cells was produced at lower concentrations than those required for affecting osteosarcoma cells directly [8].
According to Hanahan, low-dose metronomic schedules exert a non-cytotoxic effect on the tumor environment that might be related to angiogenesis and vasculogenesis [9]. Patients with metastatic esophageal carcinoma have few therapeutic options. Fluorouracil is one of the most widely used drugs, why capecitabine was chosen. Capecitabine is easy to administer and does not require hospital admission. In this situation, where the aim of treatment is to sustain good quality of life, it is important that the treatment is well tolerated and has minimal impact on daily life. We believe that this case presentation is an interesting example of successful palliative treatment in a setting where treatment options are highly limited and that this approach deserves further exploration.
References
[1] Bottini A, Generali D, Brizzi MP, Fox S, Bersiaga A, Berruti A, et al. Randomized Phase II trial of Letrozole and Letrozole plus low-dose metronomic oral Cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol 2006;/24:/36238.
[6] Vacca A, Iurlaro M, Ribatti D, Minischetti M, Nico B, Dammacco F, et al. Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood 1999;/94:/414355.
[7] Klement G, Baruchel S, Rak J, Man S, Clark K, Kerbal R, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;/105:/R1524.
[8] Tomoda R, Seto M, Hioki Y, Sonoda J, Matsumine A, Uchida A, et al. Low-dose methotrexate inhibits lung metastasis and lengthens survival in rat osteosarcoma. Clin Exp Metastasis 2005;/22:/55964.
[9] Hanahan D, Bergers G, Bergsland E. Less is more, regularly: Metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;/105:/10457.868 H. Carstens and M. Albertsson Acta Oncol Downloaded from informahealthcare.com by 173.53.243.92
For personal use only.
Cancer Chemother Pharmacol. 2009 Jun;64(1):189-93. Epub 2009 Jan 17. To widen the setting of cancer patients who could benefit from metronomic capecitabine.
Nannini M, Nobili E, Di Cicilia R, Brandi G, Maleddu A, Pantaleo MA, Biasco G.
Department of Hematology and Oncology Sciences LA Seragnoli, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. maggie.nannini@gmail.com
PURPOSE: We investigated the efficacy and toxicity of metronomic capecitabine administered at a fixed dose of 1,000 mg daily in three elderly or poor performance status patients with advanced colorectal cancer (CRC) and gastric cancer. METHODS: In this study a pretreated advanced CRC patient (patient 1), a not previously treated advanced gastric cancer patient (patient 2), and a not previously treated advanced rectal cancer patient (patient 3) were given metronomic capecitabine administered at a fixed dose of 1,000 mg daily (day 1-28 continuously). The efficacy was evaluated every 3 months by instrumental evaluation and the treatment was continued until progression of disease or toxicity. RESULTS: A stable disease was observed in all three patients. The duration of treatment was above 3 months and no major toxicities occurred. CONCLUSIONS: Our results indicate that metronomic capecitabine may be considered a safe and valid treatment option for advanced CRC and gastric cancer patients, both after failure of previous lines of chemotherapy or in front-line when standard chemotherapy is contraindicated, especially when the aim of medical treatment is to achieve disease control and to arrest tumour growth without affecting the patient's quality of life. Nevertheless, further clinical studies, as well as a greater clinical experience are required in order to better define the role of this strategy in medical oncology.
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
Maybe "mabs" and metronomics are compatible:
YM BIOSCIENCES ANNOUNCES NIMOTUZUMAB RESULTS IN ADVANCED TRIPLE-NEGATIVE BREAST CANCER MODEL PRESENTED AT AACR-NCI-EORTC MEETING MISSISSAUGA, ON, Nov. 18 /PRNewswire-FirstCall/ - YM BioSciences Inc. (NYSE Amex: YMI; TSX: YM), a life sciences product development company that identifies and advances a diverse portfolio of promising cancer-related products at various stages of development, announced that results from a study evaluating nimotuzumab were presented today in a poster at the 2009 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference in Boston, Massachusetts. The reported results demonstrate that nimotuzumab in combination with metronomic chemotherapy in an advanced triple-negative breast cancer preclinical model is safe and effective.
In this study nimotuzumab, an epidermal growth factor receptor (EGFR) targeting antibody, was administered twice weekly in combination with metronomic (continuous low-dose) cyclophosphamide. This regimen resulted in significant primary tumor growth delay in an aggressive, metastatic, higher EGFR-expressing variant of the MDA-MB-231 human breast cancer breast model, which over-expresses EGFR. In addition, the combination resulted in a significant survival advantage over cyclophosphamide alone.
"The data demonstrate that nimotuzumab in combination with metronomic cyclophosphamide is safe and effective in this aggressive tumor type which has limited therapeutic options. Furthermore, the addition of nimotuzumab would be expected to be minimally toxic to patients and as such, this combination should be considered for this patient population in future clinical trials," said lead author Dr.
Anthony J. Mutsaers of the Division of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre and Department of Medical Biophysics, University of Toronto.
The research poster is entitled "Combination treatment with metronomic cyclophosphamide and the EGFR monoclonal antibody nimotuzumab is efficacious and non-toxic in a preclinical model of advanced triple negative breast cancer". It is being presented today (Poster Session C, Abstract C49) by the author.
YM BioSciences Reports CYT997 Oral Vascular Disrupting Agent Results Presented at AACR-NCI-EORTC Meeting MISSISSAUGA, Canada – November 16, 2009 – YM BioSciences Inc. (NYSE Amex: YMI; TSX: YM),a life sciences product development company that identifies and advances a diverse portfolio of promising cancer-related products at various stages of development, announced that preclinical results for CYT997 were presented today in a poster by Cytopia Limited (ASX:CYT) at the 2009 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference in Boston, Massachusetts. CYT997 is an orally available, small molecule vascular disrupting agent (VDA) currently in Phase II clinical studies. A proposal to merge Cytopia into YM has been previously announced and is pending approval by Cytopia shareholders, Australian court and other regulatory approvals.
The results reportedly demonstrate that when administered metronomically (in frequent, low doses), CYT997 is able to produce potent vascular disrupting effects in tumors (colon adenocarcinoma xenograft model), and in combination with cisplatin dosed weekly leads to enhanced antitumor effects compared to cisplatin alone. Administration of CYT997 reportedly resulted in a time and concentration-dependent shutdown of tumor vasculature. Daily administration of CYT997 reportedly resulted in a sustained shutdown of tumour vasculature, increased necrosis and increased survival.
“The results of this study appear to demonstrate the broad potential utility of CYT997 as an anticancer agent. The ability to administer CYT997 orally differentiates it from most other VDAs in development and allows more flexible dosing regimes than would be possible for agents that can only be administered intravenously,” said Chris Burns, Director of Research of Cytopia. “Metronomic administration of a VDA may likely result in more consistent and prolonged collapse of tumor vasculature and an orally administered VDA would be ideal for this type of administration,” noted Dr. Robert Kerbel, Professor (adjunct), Cancer Biology, Medicine, MD Anderson Cancer Center, University of Texas and Professor, Medical Biophysics, University of Toronto.
Dr. Chris Burns presented the poster entitled, “Antitumour activity of CYT997: A Phase II vascular disrupting agent administered orally in combination with cisplatin in a colon adenocarcinoma xenograft mode” at the Angiogenesis and Antiangiogenesis Agents poster session on Monday, 16 November 2009.
“CYT997 is substantially distinct from the other VDAs in that it can be delivered orally, as well as intravenously, facilitating more frequent administration at lower doses, a regimen likely to enhance both its safety and efficacy. We believe this unique aspect of CYT997 could significantly expand its utility and that its development could add to existing treatment protocols and lead to new and important regimens for a wide range of tumour types,” said David Allan, Chairman and CEO of YM BioSciences.
Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity
Giannoula Klement1, Sylvain Baruchel2, Janusz Rak1, Shan Man1, Katherine Clark1, Daniel J. Hicklin3, Peter Bohlen3 and Robert S. Kerbel1 1Sunnybrook and Women's College Health Sciences Centre, Biological Sciences Program, Division of Cancer Biology Research, and Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, Ontario, Canada 2Hospital for Sick Children, Department of Pediatrics, Division of Hematology/Oncology, New Agent and Innovative Therapy Program, Toronto, Ontario M5G 1X8, Canada 3ImClone Systems Inc., New York, New York 10014, USA
Address correspondence to: Robert S. Kerbel, Sunnybrook and Women’s College Health Sciences Centre, Biological Sciences, Division of Cancer Biology Research, Room S-218, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. Phone: (416) 480-5711; Fax: (416) 480-5703; E-mail: kerbel@srcl.sunnybrook.utoronto.ca.
Published April 15, 2000
Received for publication November 2, 1999, and accepted in revised form February 25, 2000.
Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of chemotherapy in vivo and may delay or prevent the acquisition of drug-resistance by cancer cells. We have implemented a treatment regimen that augments the potential antivascular effects of chemotherapy, that is devoid of obvious toxic side effects, and that obstructs the development of drug resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) targeting the flk-1/KDR (type 2) receptor for VEGF, or both agents together. The rationale for this combination was that any antivascular effects of the low-dose chemotherapy would be selectively enhanced in cells of newly formed vessels when survival signals mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment individually resulted in significant but transient xenograft regression, diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably, the combination therapy resulted in full and sustained regressions of large established tumors, without an ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months.
This article may have been published online in advance of the print edition. The date of publication is available
from the JCI website, http://www.jci.org. J. Clin. Invest.105:R15–R24 (2000).
Dose-Dense and/or Metronomic Schedules of Specific Chemotherapies Consolidate the Chemosensitivity of Triple-Negative Breast Cancer: A Step Toward Reversing Triple-Negative Paradox
Rita S. Mehta Departments of Division of Hematology/Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California at Irvine School of Medicine, Irvine, CA
Liedtke et al1 report a progression-free survival of 63% inpatients with triple-negative breast cancer predominantly treatedwith anthracyline-based first and second regimens in the neoadjuvantsetting. They suggest that third generation regimen are importantconsiderations in triple-negative subtypes of breast cancerin their discussion, but we feel it needs to be emphasized thatthird generation regimens should be standard in treatment oftriple-negative breast cancer.
Combining the four subgroups(based additionally on progesterone receptor status and humanepidermal growth factor receptor 2 [HER-2] status) of 483 patientswith estrogen receptor–negative breast cancer, the 3-yearprogression-free survival is similarly 63% and overall survivalis 74%.1 These combined group results are comparable with the5-year progression-free survival of 63% and overall survivalof 68% in 327 patients with estrogen receptor–negativebreast cancer updated by Citron et al2 in the adjuvant setting(possibly smaller tumors, but longer time outcome) using thestandard once-every-3-weeks doxorubicin, cyclophosphamide, andpaclitaxel.
In the comparator arm, the 5-year progression-freesurvival improved statistically significantly to 70% and overallsurvival to 75% in 336 patients with estrogen receptor–negative(includes triple-negative subset) breast cancer with use ofdose-dense (once every 2 weeks) administration of doxorubicin,cyclophosphamide, and paclitaxel—a third generation regimen(23% hazard reduction).2
Another trial showed an estimated 5-yearevent-free survival of 71% in the triple-negative cohort treatedwith two cycles of dose-dense epirubicin and cyclophosphamidefollowed by high-dose cyclophosphamide, thiotepa, and epirubicinchemotherapy compared with only 26% in the four cycles of dose-denseepirubicin and cyclophosphamide followed by dose-dense cyclophosphamide,methotrexate, and flurouracil arm, but the poor survival incomparator arm suggest that rapid cycling to an alternate effectiveregimen may be the underlying mechanism of superiority of dose-denseand dose-intensified regimen.3
Similarly, weekly paclitaxelsignificantly improved the 5-year progression-free hazard rateby 40% in hormone receptor–negative (including triple-negativesubset) breast cancer and 20% in hormone receptor–positivesubsets compared with these subsets treated with once-every-3-weeksscheduling.4
A parallel phase III neoadjuvant study demonstrateda pathologic complete response of 43% with denser doxorubicin(weekly) and cyclophosphamide (continuous) compared with 26%with once-every-3-weeks doxorubicin and cyclophosphamide, botharms receiving weekly paclitaxel in locally advanced breastcancer, suggesting an additive benefit of denser administrationdoxorubicin and cyclophosphamide, in addition to the denseradministration of paclitaxel.5Taken together, studies showbenefit of accelerated schedules (weekly or once every 2 weeks)of doxorubicin, cyclophosphamide, and paclitaxel. Importantly,comparing across trials, weekly paclitaxel achieves a higherhazard rate reduction than once-every-2-weeks paclitaxel whenboth accelerated schedules are compared to once-every-3-weekspaclitaxel.2,4
Of note, Liedtke et al1 show that 22% of patients who achievedpathologic complete response had an overall survival of 94%,and 78% of patients who did not achieve a pathologic completeresponse had a 68% overall survival—a 26% difference.An absolute 50% increment in pathologic complete response overa baseline of 22% would move an additional 50% of patients from68% to 94% survival (an absolute 26% improvement for the 50%patients), a 13% increment in survival above a baseline 3-yearsurvival of 74% for 100 patients would result in overall survivalimprovement to 87% (a 25% increment in pathologic complete responsewould move 25% of patients from 68% to 94% survival, nettinga 6.5% improvement in 3-year survival; ie, each 10% incrementin pathologic complete response will translate into an absolute2.6% 3-year survival). Green et al6 show doubling of pathologiccomplete response from 23% to 48% with weekly paclitaxel, andan absolute 25% improvement of pathologic complete responsein the hormone receptor–negative subset. On projecting,this will translate into an absolute 6.5% survival benefit,that is an improved 3-year overall survival of 81.5%, a 25%hazard reduction at a minimum. Speculatively, additional survivalbenefit may accrue with increase in the minimal residual disease.6Indeed, the actual benefit in the trial reported by Sparanoet al 4 was 40% hazard reduction with weekly paclitaxel comparedto once-every-3-weeks paclitaxel in hormone receptor–negativesubset.
Of the prospectively maintained database of 14 patients withstage IIA-IIIB (including inflammatory breast cancer) or localrelapse HER-2–negative, estrogen receptor–negative,and progesterone receptor–negative, infiltrating ductalcarcinoma (excluding two patients with metaplastic carcinoma)of breast who received dose-dense doxorubicin and cyclophosphamide(maximum four doses, except one who relapsed after doxorubicin,cyclophosphamide, and flurouracil) followed either by dose-densepaclitaxel (n = 2; four doses), or by weekly paclitaxel (cremophor[80 mg/m2] or albumin bound [100 mg/m2]) with carboplatin (atarea under the curve of 2, both 3 weeks on, 1 week off; maximum12 doses, n = 12) plus or minus maximum eight doses of bevacizumabevery 2 weeks (n = 4; maximum 8 doses), 10 of 14 patients (71%;95% CI, 42% to 92%) achieved pathologic complete response. Twoadditional patients had scattered cells in the breast with nolymph node involvement. Thus, 13 of 14 (93%; 95% CI, 66% to100%) patients had no evidence of residual lymph node involvement.The progression-free survival of 86% (95% CI, 57% to 98%) andoverall survival of 93% (95% CI, 66% to 100%) of 14 patientsat a median follow-up of 36 months (range, 22 to 68 months)compared with the projected survival improvement of 87% basedon pathologic complete response of 71% is promising.
Assessedanother way, a reversal of pathologic response incidence from22% reported by Liedtke et al1 to 71% is likely to show improvementin survival closer to 94% for the majority of patients, a resultseen with our data—a 73% hazard reduction. Therefore,the high pathologic complete response reported by us parallelsthe benefit of once-every-2-weeks anthracyclines (or denser),and once-every-2-weeks or once-weekly paclitaxel schedulingin phase III trials.5,6 Faster delivery of anthracyclines allowsadministration of targeted or alternate effective treatmentearlier. For example, hormone receptor blocker for hormone receptor–positivebreast cancer, trastuzumab for HER-2–positive breast cancer,and once-weekly paclitaxel, an alternate effective treatmentfor all subsets of breast cancer, specifically triple-negativesubset. Therefore, for patients with triple-negative tumors,optimally scheduled doxorubicin and cyclophosphamide (once every2 weeks) and paclitaxel (once weekly) should be standard.2,4
As 12 of 14 patients also received carboplatin, the use of carboplatinmay be considered in any patient with large (as seen in neoadjuvantsetting) triple-negative breast cancer.7,8 While carboplatinbased adjuvant phase III studies are limited to docetaxel, trastuzumab,and carboplatin combination, extrapolation of docetaxel, trastuzumab,and carboplatin combination to paclitaxel and carboplatin (andtrastuzumab in HER-2–positive breast cancer) after anthracyclinesmay be reasonable pending large adjuvant or neoadjuvant trialsin triple-negative breast cancer. Importantly, carboplatin isstandard treatment for ovarian and lung cancer, and thereforelong-term outcome is known. Moreover, the BRCA-ness of the triple-negativetumors makes these tumors specifically susceptible to the DNA-damagingaction of carboplatin give support to our use of carboplatinin triple-negative breast cancer.9
Additional small studiesthat used platinums have similarly shown a promising outcomeeither in pathologic complete response (20% with single-agentcisplatin to 67% with platinum combination regimens) or in progression-freesurvival (75% to 84%) in triple-negative breast cancer.10-12,14-15We did not see any progression while patients were receivingchemotherapy, unlike the studies by Torissi et al10,13 wherethey show a substantial progression while patients were eitheron weekly paclitaxel or dose-dense docetaxel regimen. This maybe secondary to delayed switch to alternate effective therapyof weekly paclitaxel in the first case, or switch to a lesseffective dose-dense docetaxel switch in the second case.
The potential additional benefit of bevacizumab over optimumscheduling of standard chemotherapy needs to be tested in randomizedtrials, as the follow-up is shortest for the four patients receivingbevacizumab. While the small number, short follow-up, and heterogeneityof chemotherapy are limitations of our small study, the chemotherapywas uniformly delivered in accelerated fashion. Achievementof high pathologic complete response and the corresponding survivalbenefit tied to high pathologic complete response are the strengthsof the study. Despite a short follow-up, the follow-up wouldbe considered adequate for progression-free survival in triple-negativesubtype of breast cancer as the hazard rates of relapse arehighest in the first year, and taper off quickly after 3 years.1We emphasize that third generation chemotherapeutic regimensare the most important treatment regimens for triple-negativebreast cancer in achieving a higher pathologic complete response,and thereby higher survival, where the only current targetedtreatment is the accelerated and optimized chemotherapy thattargets the Gompertzian growth model as first shown by Nortonet al.16 Moreover, poor clinical outcome seen in patients withtriple-negative despite initial chemosensitivity as demonstratedby Carey et al17 can be overcome by consolidating the gainsobtained by initial chemosensitiviy of accelerated anthracyclineswith accelerated optimal chemotherapy, which at a minimum shouldinclude weekly paclitaxel.
Int J Exp Pathol. 2010 Feb;91(1):10-6. Low-dose metronomic chemotherapy with cisplatin: can it suppress angiogenesis in H22 hepatocarcinoma cells?
Shen FZ, Wang J, Liang J, Mu K, Hou JY, Wang YT.
Department of Oncology, Affiliated Hospital of Medical College, Qingdao University, Qingdao, China. fangzhenshen@126.com
Low-dose chemotherapy drugs can suppress tumours by restraining tumour vessel growth and preventing the repair of damaged vascular endothelial cells. Cisplatin is a broad-spectrum, cell cycle-non-specific drug, but has serious side effects if used at high doses. There have been few reports on the anti-angiogenic effects of low-dose cisplatin and hence the effect of low-dose metronomic (LDM) chemotherapy on the proliferation and neovascularization of H22 hepatocarcinoma cells is discussed in this research. The influence of LDM chemotherapy with cisplatin on human umbilical vascular endothelial cells (HUVECs) and proliferation of the HepG(2) human hepatocarcinoma cell line were measured using MTT assays. The LDM group was treated with cisplatin 0.6 mg/kg/day; the control group with saline 0.2 ml; the maximum tolerated dose (MTD) group with cisplatin 9 mg/kg/day. Vascular endothelial growth factor (VEGF) and matrix metallopeptidase 2 (MMP-2) were detected using immunohistochemical staining. A chicken chorio-allantoic membrane (CAM) model was used to check the inhibitory effect of LDM chemotherapy with cisplatin on neovascularization in vivo. Low-dose cisplatin inhibited HUVEC proliferation in a dose- and time-dependent manner, but was ineffective in inhibiting HepG(2) cell proliferation. Tumour growth was delayed in mice receiving LDM cisplatin, without apparent body weight loss, compared with mice that received MTD cisplatin. Microvessel density and expression of VEGF and MMP-2 were much lower in mice receiving LDM cisplatin than in the control and MTD groups.Continuous low-dose cisplatin suppressed CAM angiogenesis in vivo. LDM chemotherapy with cisplatin can inhibit the growth of blood vessel endothelial cells in vitro and shows anti-angiogenic ability in vivo.
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
Ann N Y Acad Sci. 2009 Oct;1177:2-8. Regulation of vascularization by hypoxia-inducible factor 1.
Semenza GL.
Vascular Program, Institute for Cell Engineering; McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland 21205, USA. gsemenza@jhmi.edu
Vascularization and vascular remodeling represent critical adaptive responses to tissue hypoxia that are mediated by hypoxia-inducible factor 1 (HIF-1). In patients with peripheral arterial disease, these responses are impaired by aging and diabetes, leading to critical limb ischemia and amputation. Intramuscular injection of an adenovirus encoding a constitutively active form of the HIF-1alpha subunit (CA5) increases the recovery of blood flow following femoral artery ligation in a mouse model of age-dependent critical limb ischemia. Intradermal injection of a plasmid encoding CA5 promotes healing of cutaneous wounds in a mouse model of diabetes. In cancer, vascularization is required for tumors to grow beyond microscopic size, a process that involves HIF-1-dependent production of angiogenic growth factors. Daily treatment of prostate cancer xenograft-bearing mice with low-dose anthracycline (doxorubicin or daunorubicin) chemotherapy inhibits HIF-1 DNA-binding activity, HIF-1-dependent expression of angiogenic growth factors, mobilization of circulating angiogenic cells, and tumor vascularization, thereby arresting tumor growth.
PMID: 19845601 [PubMed - indexed for MEDLINE]
Low-dose anthracyclines may block HIF-1 and stop tumor growth.
Hede K.
PMID: 19276456 [PubMed - indexed for MEDLINE]Free Article
Includes inset "Digoxin as Anticancer Agent: The HIF-1 Connection"
Quote:
A recent study suggests that the well-known anthracycline chemotherapeuticagents doxorubicin and daunorubicin, when given in small doses,can reduce tumor vascularization in animal models. The discovery,by Gregg Semenza, M.D., Ph.D., and his colleagues at Johns HopkinsUniversity School of Medicine in Baltimore, reveals a new mechanismof action for these mainstays of chemotherapy and explains whysmaller doses of chemotherapy agents given over a longer periodcan sometimes inhibit formation of new blood vessels.
Anthracyclines kill cancer cells by interfering with DNA replicationin actively dividing cells. But Semenza and his colleagues demonstratethat the drugs also interfere with a key regulator of oxygenmetabolism, hypoxia-inducible factor 1 (HIF-1), a crucial regulatorof vascularization.
Semenza discovered HIF-1 in 1992 in cells grown in low-oxygen(hypoxic) conditions and demonstrated that HIF-1 regulated theadaptation to the hypoxic growth conditions common in many solidtumors. HIF-1, a transcription factor, is a master regulatorthat activates vascular endothelial growth factor (VEGF) andmany other adaptive proteins, allowing cells to generate fuelunder hypoxic conditions.
In the present study, published in late January 2009 in theProceedings of the National Academy of Sciences online edition,he shows that chronic inhibition of HIF-1 can effectively blocktumor growth by blocking angiogenesis in a mouse xenograft model.
"When we treat [mice] with these drugs, almost immediately weinhibit HIF-1 activity, we inhibit the production of angiogeniccytokines such as VEGF, we inhibit the mobilization of angiogeniccells into the circulation, and we block tumor vascularization,"said Semenza. "At least in these xenograft models, when youblock tumor vascularization, you block tumor growth." Master Regulator
In recent years, HIF-1 has emerged as a critical regulator ofcancer growth, progression, and metastasis. High HIF-1 levelsin tumor cells have been linked to poor patient outcomes inbladder, breast, cervical, endometrial, lung, and pancreaticcancers, among others. HIF-1 enables tumor cells to thrive underthe hypoxic conditions that have been the bane of oncologiststrying to wipe out cancer cells remaining after radiation andchemotherapy.
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
Really interesting why most oncs are not trying this continuous low dose approach. As i have posted before my new onc initially offered me low dose xeloda with 3 weekly herceptin but under peer pressure withdrew the offer saying it would affect tmy quality of life! Going to have another go next week!
Elllie
Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi
Anticancer Res. 2004 May-Jun;24(3a):1759-63. Antiangiogenic potency of various chemotherapeutic drugs for metronomic chemotherapy.
Drevs J, Fakler J, Eisele S, Medinger M, Bing G, Esser N, Marmé D, Unger C.
Department of Medical Oncology, Tumor Biology Center, Freiburg, Germany. drevs@tumorbio.uni-freiburg.de
From previous preclinical findings continuous low dose (metronomic) chemotherapy is thought to inhibit tumor angiogenesis. This suggests that activated endothelial cells may be more sensitive to chemotherapeutic drugs than tumor cells. Therefore, we assessed the IC50 for several relevant chemotherapeutic drugs in different endothelial and tumor cell lines to identify optimal compounds to be used for metronomic therapy in a murine renal cell carcinoma model. Adriamycin, idarubicin, 5-fluorouracil, paclitaxel and etoposide were chosen for our studies because of their oral availability in patients or previous reports on metronomic potential. IC50s were determined by BrdU cell growth assay after short time as well as long term exposure of the following cell lines: human endothelial cells (HdmVEC/HUVEC), human breast cancer (Mcf-7), melanoma (Skmel), liver cancer (Huh7/Alexander), lung cancer (A549/LXFL), colon cancer (Dld) and murine renal cell carcinoma (RENCA). In addition, FACS analysis was performed to determine the effect on cell cycle. In vivo, doses of 2x12 mg/kg, 2x1.2 mg/kg and 10x0.24 mg/kg adriamycin were applied to 12 RENCA mice each and antitumor as well as antiangiogenic effects were assessed 21 days after tumor cell application. Independent of the exposure time, all chemotherapeutic drugs were more active against the endothelial cell lines. IC50s were significantly lower in endothelial cells (4.02E-06 to 6.16E-14 M) as compared to tumor cells (7.44E-02 to 1.9E-11 M). Cell cycle analysis of all chemotherapeutic drugs revealed a G1-arrest in endothelial cells. Adriamycin applied in metronomic doses of 10x0.24 mg/kg showed significant antiangiogenic activity whereas, in contrast, the application of 2x12 mg/kg significantly increased the vessel density in primary tumors. In summary, all chemotherapeutic agents were more active against endothelial cells in comparison to tumor cells. The hypothesis of an antiangiogenic active metronomic therapy could be confirmed in vivo by the use of adriamycin in RENCA.
PMID: 15274352 [PubMed - indexed for MEDLINE]
Ann Oncol. 2008 Feb;19(2):212-22. Epub 2007 Nov 15. Effective oral chemotherapy for breast cancer: pillars of strength.
Findlay M, von Minckwitz G, Wardley A.
Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand. mp.findlay@auckland.ac.nz
Traditionally, anticancer therapy has been dominated by intravenous drug therapy. However, oral agents provide an attractive approach to chemotherapy and use of oral treatments is increasing. We discuss the benefits and challenges of oral chemotherapy from the perspectives of patients, healthcare providers and healthcare funders. Important issues include patient preference, efficacy, compliance, bioavailability, reimbursement, use in special patient populations, financial and staff time savings and flexibility of dosing. We review data for traditional oral agents (e.g. cyclophosphamide, methotrexate), newer oral chemotherapies (e.g. capecitabine), oral formulations of traditionally intravenous agents (e.g. vinorelbine, idarubicin) and new biologic agents under evaluation in breast cancer (e.g. tyrosine kinase inhibitors). Lastly, we review studies of all-oral combination regimens. The wealth of data available and the increasing use of oral agents in breast cancer suggest that many of the concerns and perceptions about oral therapy, including efficacy and bioavailability, have been overcome, and that oral therapy will play a major role in breast cancer management in the future in both the metastatic and adjuvant settings.
Innovative schedule of oral idarubicin in elderly patients with metastatic breast cancer: comprehensive results of a phase II multi-institutional study with pharmacokinetic drug monitoring
D. Crivellari1*, D. Lombardi1, G. Corona2, C. Massacesi5, R. Talamini3, R. Sorio1, M. D. Magri1,
C. Lestuzzi4, A. Lucenti6, A. Veronesi1 & G. Toffoli2
1Division of Medical Oncology C, Centro di Riferimento Oncologico, Aviano; 2Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico,
Aviano; 3Epidemiology and Biostatistic Unit, Centro di Riferimento Oncologico, Aviano; 4Cardiology Unit, Centro di Riferimento Oncologico, Aviano;
5Division of Medical Oncology, Umberto Io Hospital, Ancona; 6Division of Medical Oncology, General Hospital, Trento, Italy
Received 10 November 2005; revised 6 January 2006; accepted 9 January 2006
Background: To determine if protracted low-dose oral idarubicin (IDA), feasible in a previous dose-finding study, would result in similar activity and a better toxicity profile in patients with metastatic breast cancer.
Patients and methods: Elderly women (‡65 years) with metastatic breast carcinoma were treated with 7.5 mg/day for 21 consecutive days, every 4 weeks. After the first fourteen patients, due to excessive toxicity, the protocol was amended to 5 mg/day. IDA and Idarubicinol (IDOL) plasma concentrations (Ctrough) were investigated in all patients.
Results: Between April 1999 and June 2004, 47 elderly patients were accrued in this two-part study (14 and 33 patients respectively). The median age was 74 and 75 years respectively. Visceral involvement was present in most patients. A partial response was noted in 7/31 patients (22%; 95% CI, 9.6–41.1%). Eleven patients had stable disease
(33%). At the dose of 5 mg/day the treatment was well tolerated. Neutropenia grade 4 was present in only 6% of patients; alopecia > grade 1 and cardiotoxicity did not occur. The median time to progression was 3 months and the median overall survival was 17 months. IDA Ctrough and IDOL Ctrough levels were significantly associated with haematologic toxicity. Conclusion: This study shows that idarubicin at the dose of 5 mg/day for 21 consecutive days is feasible and effective in elderly breast cancer patients but do not demonstrate an improvement in efficacy. A determination of the IDA and IDOL plasma levels (Ctrough) is predictive for toxicity.
"In conclusion, even though our results with this new oral drug schedule confirm previous data on the activity of IDA but do not demonstrate an improvement in efficacy, the opportunity to utilise the schedule should not be underestimated."
Ministero della Salute (2005-conv 93)
metronomic docetaxel
on hormone refractory prostate carcinoma cells. In vitro, metronomic therapy lowered tumor cell viability, inducing apoptosis and reducing the invasive potential at 10- to100-fold lower concentrations as compared with the maximum tolerated dose. Metronomic regimens resulted in a significant reduction of vascular endothelial cell growth factor expression and up-regulation of endogenous angiogenesis inhibitors. Our studies suggest that heterogeneous nuclear ribonucleoprotein K is a mediator of the effects we observed. Targeting heterogeneous nuclear ribonucleoprotein K may serve as a specific antimetastasis and antiangiogenic therapy and could be a potential predictive marker to determine the optimal dose and schedule for metronomic chemotherapy regimens. These findings highlight the multiple effects that may characterize antiangiogenic metronomic chemotherapy and suggest that docetaxel might act as antitumor compound by affecting both cancer and endothelial cells at the same drug concentration. Careful optimization of drug scheduling and dosages will be required to maximize antitumor responses with metronomic approaches. © 2009 UICC 
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24 weeks) occurred in eight patients, for an overall clinical benefit (CR + PR + SD 
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