[Rich66]

Metronomic Chemotherapy Enhances the Efficacy of Antivascular Therapy in Ovarian Cancer
http://cancerres.aacrjournals.org/cg...tract/67/1/281 (PDF attached below)

Aparna A. Kamat¹, Tae Jin Kim^1,5, 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. Sood^1,3 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 low doses of chemotherapeutic agents targeting tumor-associated endothelial cells. We examined the efficacy of metronomic taxanes alone and in combination with AEE788—a dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitor—in an orthotopic mouse model of ovarian cancer. Growth-modulating effects of metronomic and maximum tolerated dose (MTD) regimens on overall survival were tested.
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In vivo, metronomic docetaxel resulted in significant reduction of tumor growth in the taxane-sensitive cell lines, whereas metronomic docetaxel plus AEE788 had an additive effect resulting in significant prolongation in survival. Combination therapy was effective even in the taxane-resistant model. Metronomic chemotherapy alone and combined with AEE788 resulted in a decrease in the proliferative index and microvessel density of treated tumors, whereas combination therapy increased the apoptotic index (P < 0.001). In vitro, metronomic taxanes caused endothelial cell toxicity at 10- to 100-fold lower concentrations compared with MTD dosing. Metronomic regimens inhibited mobilization of CEPs (P < 0.05) and led to a decrease in cell-free DNA levels (P < 0.05). Our results suggest that metronomic taxane chemotherapy with dual EGFR and VEGFR inhibition is highly efficacious and should be considered for future clinical trials. [Cancer Res 2007;67(1):281–8]


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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).
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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.
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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]