preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survival

[Rich66]

Clin Cancer Res. 2009 Dec 8. [Epub ahead of print]
Predictive Potential of Angiogenic Growth Factors and Circulating Endothelial Cells in Breast Cancer Patients Receiving Metronomic Chemotherapy Plus Bevacizumab.
Calleri A, Bono A, Bagnardi V, Quarna J, Mancuso P, Rabascio C, Dellapasqua S, Campagnoli E, Shaked Y, Goldhirsch A, Colleoni M, Bertolini F.

Authors' Affiliations: Laboratory of Hematology-Oncology, Medical Senology Research Unit and Division of Medical Oncology, Departments of Pathology and Medicine, European Institute of Oncology; Division of Epidemiology and Biostatistics, European Institute of Oncology, and Department of Statistics, University of Milan-Bicocca, Milan, Italy; and Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
PURPOSE: The association of chemotherapy and antiangiogenic drugs has shown efficacy in clinical oncology. However, there is a need for biomarkers that allow selection of patients who are likely to benefit from such treatment and are useful for indicating best drug combination and schedule. EXPERIMENTAL DESIGN: We investigated the predictive potential of six angiogenic molecules/transcripts and nine subpopulations of circulating endothelial cells (CEC) and progenitors (CEP) in 46 patients with advanced breast cancer treated with metronomic cyclophosphamide and capecitabine plus bevacizumab. RESULTS: Median time to progression was 281 days. Baseline CECs higher than the first quartile were associated with an increased time to progression (P = 0.021). At progression, CECs were markedly reduced (P = 0.0002). In the cohort of 15 long-term responders, who progressed later than 1 year after beginning of therapy, circulating vascular endothelial growth factor (VEGF)-A levels measured after 2 months of therapy were significantly reduced, and there were significant trends toward lower levels of PDGF-BB, CEPs, and CECs. At the time of progression, angiogenic growth factors VEGF-A and basic fibroblast growth factor were significantly increased. CONCLUSIONS: Baseline CECs (likely reflecting an active vascular turnover) predicted a prolonged clinical benefit. At the time of relapse, a pattern of decreased CECs and increased angiogenic growth factors suggested a switch toward a different type of cancer vascularization. VEGF-A and basic fibroblast growth factor levels after 2 months of therapy were also useful to identify patients whose disease was likely to progress. These biomarkers are likely to be useful for treatment selection and might be incorporated in design of future studies. (Clin Cancer Res 2009;15(24):7652-7).

PMID: 19996223


Approach that exploits pro-angionenic weekly therapy:

Curr Cancer Drug Targets. 2009 Sep;9(6):777-88.
Increased tumor oxygenation and drug uptake during anti-angiogenic weekly low dose cyclophosphamide enhances the anti-tumor effect of weekly tirapazamine.

Doloff JC, Khan N, Ma J, Demidenko E, Swartz HM, Jounaidi Y.
Department of Biology, Boston University, MA 02215, USA.
Metronomic cyclophosphamide treatment is associated with anti-angiogenic activity and is anticipated to generate exploitable hypoxia using hypoxia-activated prodrugs. Weekly administration of tirapazamine (TPZ; 5 mg/kg body weight i.p.) failed to inhibit the growth of 9L gliosarcoma tumors grown s.c. in scid mice. However, the anti-tumor effect of weekly cyclophosphamide (CPA) treatment (140 mg/kg BW i.p.) was substantially enhanced by weekly TPZ administration. An extended tumor free period and increased frequency of tumor eradication without overt toxicity were observed when TPZ was given 3, 4 or 5 days after each weekly CPA treatment. Following the 2(nd) CPA injection, Electron Paramagnetic Resonance (EPR) Oximetry indicated significant increases in tumor pO(2), starting at 48 hr, which further increased after the 3(rd) CPA injection. pO(2) levels were, however, stable in growing untreated tumors. A strong negative correlation (-0.81) between tumor pO(2) and tumor volume during 21 days of weekly CPA chemotherapy was observed, indicating increasing tumor pO(2) with decreasing tumor volume. Furthermore, CPA treatment resulted in increased tumor uptake of activated CPA. CPA induced increases in VEGF RNA, which reached a maximum on day 1, and in PLGF RNA which was sustained throughout the treatment, while anti-angiogenic host thrombospondin-1 increased dramatically through day 7 post-CPA treatment. Weekly cyclophosphamide treatment was anticipated to generate exploitable hypoxia. However, our findings suggest that weekly CPA treatment induces a functional improvement of tumor vasculature, which is characterized by increased tumor oxygenation and drug uptake in tumors, thus counter-intuitively, benefiting intratumoral activation of TPZ and perhaps other bioreductive drugs.

PMID: 19754361 [PubMed - indexed for MEDLINE]





Cancer Invest. 2010 Jan;28(1):74-84.
Low-dose metronomic paclitaxel chemotherapy suppresses breast tumors and metastases in mice.

Jiang H, Tao W, Zhang M, Pan S, Kanwar JR, Sun X.
The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China.

This study investigated the use of low-dose metronomic (LDM) chemotherapy with paclitaxel in a highly metastatic mouse model of 4T1 breast cancers, and compared it with the maximum tolerable dose (MTD) therapy. LDM therapy displayed a stronger anti-tumor activity in suppressing primary and metastatic breast tumors with less degree of side effects, and stronger anti-angiogenic and anti-lymphangiogenic activities than MTD therapy. But MTD therapy showed stronger pro-apoptotic and anti-proliferative activities in situ. Paclitaxel therapy downregulated expression of vascular endothelial growth factor receptor-2 (VEGFR2) and up-regulated expression of thrombospondin-1. The results support the application of paclitaxel LDM therapy to treat advanced breast cancer.

PMID: 20001297 [PubMed - in process]




an oral, brain barrier crossing, Anthracycline amenable to metromic delivery:


Penetration of Idarubicin into Malignant Brain Tumor Tissue
Authors: Boogerd W.¹; Tjahja I.S.²; van de Sandt M.M.³; Beijnen J.H.⁴
Source: Journal of Neuro-Oncology, Volume 44, Number 1, August 1999 , pp. 65-69(5)
Publisher: Springer
Abstract:
Anthracyclines are effective in breast cancer and have in vitro cytotoxicity in glioma. In patients with glioma anthracyclines are not effective possibly because the hydrophilic drugs do not reach cytotoxic levels in tumor tissue. Idarubicin is more lipophilic than the other anthracyclines and is more cytotoxic in glioma cell lines. The uptake of idarubicin and its major metabolite idarubicinol in brain tumor tissue were measured in a patient with a brain metastasis from breast cancer and in 4 patients with malignant glioma after an oral dose of idarubicin (45 mg/m^2 in 1 patient; 25 mg/m^2 in 4 patients), given 15–24 h before brain tumor resection. The concentrations of idarubicin and of idarubicinol in tumor tissue exceeded the concurrent plasma concentrations as well as the peak plasma concentrations in all cases. The median tumor: concurrent plasma ratio of idarubicinol was 5.7 (range 1.7–18). The concentration of idarubicinol in the marginal zone between brain and tumor tissue was lower than in central tumor tissue, but was still higher than the plasma concentration in 2 of the 3 examined cases. Bone marrow suppression (platelets CTC grade 2, granulocytes CTC grade 4) occurred after a single dose of 45 ml/m^2. No toxicity was seen at a dose of 25 mg/m^2. These results, the in vitro activity of idarubicin in glioma, the convenience of oral administration, and its toxicity profile make clinical studies with idarubicin in malignant glioma, and perhaps also in brain metastases from breast cancer worthwhile.
1: Department of Neurology, Slotervaart Hospital, Amsterdam; Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands
2: Department of Neurosurgery, Slotervaart Hospital, Amsterdam 3: Department of Pathology, Slotervaart Hospital, Amsterdam
4: Department of Pharmacy, Slotervaart Hospital, Amsterdam; Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands



Ann Oncol. 2006 May;17(5):807-12. Epub 2006 Feb 23.
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.

Crivellari D, Lombardi D, Corona G, Massacesi C, Talamini R, Sorio R, Magri MD, Lestuzzi C, Lucenti A, Veronesi A, Toffoli G.
Division of Medical Oncology C, Centro di Riferimento Oncologico, Aviano, Italy. dcrivellari@cro.it
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 (> or=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 (C(trough)) 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 C(trough) and IDOL C(trough) 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 (C(trough)) is predictive for toxicity.

PMID: 16497825 [PubMed - indexed for MEDLINE]





Pediatr Blood Cancer. 2009 Dec 4. [Epub ahead of print]
Second complete remission of relapsed medulloblastoma induced by metronomic chemotherapy.

Sterba J, Pavelka Z, Andre N, Ventruba J, Skotakova J, Bajciova V, Bronisova D, Dubska L, Valik D.
Pediatric Oncology Department, University Hospital Brno, Masaryk University Brno, Brno, Czech Republic.
Prognosis for children with relapsed medulloblastoma remains poor. Metronomic chemotherapy may offer some benefit to patients treated initially with intensive regimens. However, dosing and duration of such palliative treatment have not been systematically studied. Here we describe a child with medulloblastoma relapsing after initial high-dose chemotherapy and standard radiotherapy. The patient was then treated with metronomic chemotherapy and achieved second complete remission after 21 months of treatment. Three months off therapy he relapsed again and died from progressive disease. This case illustrates the potential benefit of metronomic chemotherapy but also shows the uncertainty of when to stop metronomic chemotherapy while balancing toxicity.

Pediatr Blood Cancer. (c) 2009 Wiley-Liss, Inc.

PMID: 19967772 [PubMed - as supplied by publisher]





J Neurooncol. 2010 Jan 12. [Epub ahead of print]
Metronomic treatment of malignant glioma xenografts with irinotecan (CPT-11) inhibits angiogenesis and tumor growth.

Takano S, Kamiyama H, Mashiko R, Osuka S, Ishikawa E, Matsumura A.
Department of Neurosurgery, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba city, Ibaraki, 305-8575, Japan, shingo4@md.tsukuba.ac.jp.
Irinotecan (CPT-11) has shown emerging promise in the treatment of malignant gliomas. It is believed the mechanism of action of irinotecan is to sensitize glioma cells to the cytotoxic action of radiation therapy and alkylating agents. However, clinical trials using weekly or three-weekly doses of CPT-11 have demonstrated imaging responses in only 10-15% of patients. In this study, we evaluated another mechanism of action, angiosuppression by CPT-11 of ACNU-resistant gliomas, using a metronomic administration schedule. Two different types of treatment, (1) conventional and (2) metronomic, were applied to the subcutaneous U87 model. We found that metronomic administration of CPT-11 significantly inhibited malignant glioma growth by inhibiting angiogenesis; this treatment procedure reduced the number of tumor vessels and the area of hypoxic lesions and reduced expression of VEGF and HIF-1alpha, the most important angiogenic factors in gliomas. Metronomic treatment was superior to conventional treatment with regard to the severe systemic side effect of body weight loss. The growth inhibitory effect was very similar for both low and high doses of CPT-11. These angiosuppressive effects of CPT-11 show promise for another use of CPT-11 in metronomic and scheduled angiosuppressive chemotherapy with low dose and long-term administration for malignant gliomas without systemic side effects.