Metronomic Paclitaxel Research Articles

Efficacy of granulocyte-macrophage colony-stimulating factor combined with metronomic paclitaxel in the treatment of Lewis lung carcinoma transplanted in mice.

Metronomic chemotherapy in combination with immunotherapy is an attractive approach in cancer therapy. The purpose of the present study was to investigate the anti-tumor effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with metronomic paclitaxel (MET PTX) on Lewis lung carcinoma transplanted in mice. In the present study, tumor-bearing mice survival time and tumor growth were monitored. The day after the end of the treatment, white blood cells were counted, and the number and maturation of dendritic cell were determined by flow cytometry. Besides, microvessel density and tumor cell proliferation were determined by immunohistochemistry, while apoptosis was determined by TUNEL (Terminal deoxynucleotidyl transferase-mediated nick end labeling) assay. Micro 18F-FDG PET/CT (18F-Fluorodeoxyglucose positron emission tomography/computed tomography) was used to obtain SUVmax values. White blood cells reduction was not observed in the mice treated with GM-CSF combined with MET PTX. Moreover, GM-CSF combined with MET PTX further reduced proliferation and microvessel density, promoted tumor apoptosis, increased the dendritic cells number and induced their maturation, with concomitant delay in tumor growth and improved survival. Taken together, GM-CSF combined with MET PTX exerted a synergistic anti-tumor effect against lung cancer in a mouse model through an antiangiogenic activity and inducing dendritic cells maturation without exerting pronounced adverse effects. Hence, combined metronomic chemotherapy and immunotherapy could be a potential strategy for the treatment of patients with advanced lung cancer.

Knockdown of Hypoxia-Inducible Factor 1α Improved the Efficacy of Low-Dose Metronomic Chemotherapy of Paclitaxel in Human Colon Cancer Xenografts.

Low-dose metronomic chemotherapy represents a new strategy for solid tumor treatments with a strong antiangiogenic activity and few side effects. However, low-dose metronomic therapy alone is not always as effective as traditional chemotherapy on eradication of tumor. On the contrary, low-dose metronomic in some cases could stimulate tumor growth due to hypoxia of tumor cells induced during therapy. Our study aimed to investigate whether knockdown of hypoxia-inducible factor-1α expression in tumor cell could facilitate low-dose metronomic therapy with paclitaxel for human colon cancer. Human colon cancer cell line (HT-29) stably transfected with specific short hairpin RNAs silencing hypoxia-inducible factor-1α exhibited marked attenuation of hypoxia-induced expression of the target genes such as vascular endothelial growth factor, glucose transporter 1, and P-glycoprotein. Compared with HT-29-c xenograft tumor model established by subcutaneous injection of HT-29 cells stably transfected with scrambled control short hairpin RNA, HT-29-ih xenograft tumor model showed more significant and long-lasting antitumor responses of empirical metronomic paclitaxel regimens, accompanied by drastic angiogenesis decrease and neglectable toxicity. All these data indicated that the combination of paclitaxel low-dose metronomic therapy with hypoxia-inducible factor-1α knockdown might provide a potent battle against colon cancer.

Low-Dose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma.

Nuclear expression of the calcium-binding protein S100A4 is a biomarker of increased invasiveness in cholangiocarcinoma, a primary liver cancer with scarce treatment opportunities and dismal prognosis. In this study, we provide evidence that targeting S100A4 nuclear import by low-dose paclitaxel, a microtubule-stabilizing agent, inhibits cholangiocarcinoma invasiveness and metastatic spread. Administration of low-dose paclitaxel to established (EGI-1) and primary (CCA-TV3) cholangiocarcinoma cell lines expressing nuclear S100A4 triggered a marked reduction in nuclear expression of S100A4 without modifying its cytoplasmic levels, an effect associated with a significant decrease in cell migration and invasiveness. While low-dose paclitaxel did not affect cellular proliferation, apoptosis, or cytoskeletal integrity, it significantly reduced SUMOylation of S100A4, a critical posttranslational modification that directs its trafficking to the nucleus. This effect of low-dose paclitaxel was reproduced by ginkolic acid, a specific SUMOylation inhibitor. Downregulation of nuclear S100A4 by low-dose paclitaxel was associated with a strong reduction in RhoA and Cdc42 GTPase activity, MT1-MMP expression, and MMP-9 secretion. In an SCID mouse xenograft model, low-dose metronomic paclitaxel treatment decreased lung dissemination of EGI-1 cells without significantly affecting their local tumor growth. In the tumor mass, nuclear S100A4 expression by cholangiocarcinoma cells was significantly reduced, whereas rates of proliferation and apoptosis were unchanged. Overall, our findings highlight nuclear S100A4 as a candidate therapeutic target in cholangiocarcinoma and establish a mechanistic rationale for the use of low-dose paclitaxel in blocking metastatic progression of cholangiocarcinoma. Cancer Res; 76(16); 4775-84. ©2016 AACR.

Tolerance of weekly metronomic paclitaxel and carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer patients who are unlikely to tolerate 3 weekly paclitaxel and carboplatin

Objective:There are little data regarding safety and effectiveness of neoadjuvant chemotherapy (NACT) in patients who are considered unfit for receiving 3 weekly paclitaxel and carboplatin. The aim of this study was to examine the toxicity and response rates of weekly paclitaxel and carboplatin as NACT in such cohort of patients.Methods:Study population included advanced ovarian cancer patients who were unlikely to tolerate 3 weekly paclitaxel and carboplatin and hence received weekly paclitaxel (80 mg/m2) and carboplatin AUC-2 as NACT. The data regarding the baseline characteristics, chemotherapy tolerance, completion rates, toxicity (Common Terminology Criteria for Adverse Events version 4.02), and radiological response rates are presented. SPSS version 16 was used for analysis. Descriptive statistics is presented.Results:Eleven patients received this schedule. Nine patients completed nine cycles of NACT. Except one, all patients completed NACT with an average relative dose intensity of >0.8. There was no chemotherapy-related mortality. Grade 3–4 life-threatening complications were seen in two patients. The post NACT response rate was 100%.Conclusions:Weekly paclitaxel and carboplatin chemotherapy is safe and efficacious in patients who are unsuitable for 3 weekly paclitaxel and carboplatin chemotherapy schedules.

Decrease of let-7f in low-dose metronomic Paclitaxel chemotherapy contributed to upregulation of thrombospondin-1 in breast cancer.

Low-dose metronomic (LDM) paclitaxel therapy displayed a stronger anti-angiogenic activity on breast tumors with fewer side effects. Upregulation of anti-angiogenic factor Thrombospondin-1 (TSP-1) accords for therapeutic potency of LDM paclitaxel, but its molecular mechanism has not been elucidated yet. microRNAs (miRNAs) have emerged as new important regulators of tumor growth and metastasis. Here, we hypothesize that miRNAs are involved in TSP-1 overexpression in paclitaxel LDM therapy of breast tumors. The miRNA profile of tumor tissues from control, LDM and MTD groups in 4T1 mouse breast cancer model was detected by microarray, and then verified by quantitative real-time PCR (qRT-PCR). Luciferase assay and western blot were employed to explore the mechanisms of miRNAs involved in this process. We found that let-7f, let-7a, miR-19b and miR-340-5p were reduced by >2 fold, and miR-543* and miR-684 were upregulated by at least 50% in paclitaxel LDM therapy. qRT-PCR verification revealed that let-7f level was reduced most significantly in LDM therapy. Computational prediction using TargetScan and miRanda suggested THBS1 which encodes TSP-1 as a potential target for let-7f. Luciferase activity assay further confirmed that let-7f may bind to 3'UTR of THBS1 gene and inhibit its activity. Moreover, forced expression of let-7f led to a decrease of TSP-1 at both mRNA and protein levels in MCF-7 cells. Contrastly, let-7f inhibition induced an increased expression of THBS1 mRNA and TSP-1 protein, but did not affect the proliferation and apoptosis of MCF-7 cells. Paclitaxel LDM therapy led to a decrease of let-7f and the elevation of TSP-1 protein expression in MCF-7 cells, while overexpression of let-7f may abolish LDM-induced the upregulation of TSP-1 in MCF-7 cells. In summary, let-7f inhibition contributed to the upregulation of TSP-1 in paclitaxel LDM therapy, independently of proliferation, cell cycle arrest and apoptosis of breast cancer. This study indicates let-7f as a potential therapeutic target for breast tumor.

Abstract 2995: Metronomic albumin-bound paclitaxel and topotecan has potent antitumor activity in ovarian cancer

Abstract Objective: There is growing recognition of the important role of metronomic chemotherapy for cancer treatment. Based on their unique anti-angiogenic effects, we tested the efficacy of dual albumin-bound paclitaxel (ABP), which stimulates Thrombospondin-1, and topotecan, which inhibits Hypoxia-inducible factor 1-α, chemotherapy at metronomic dosing in ovarian carcinoma. Methods: We examined the effects of ABP and topotecan in vitro (MTT) and in vivo using SKOV3ip1, HeyA8 and HeyA8-MDR orthotopic mouse models of ovarian cancer. We also examined effects on proliferation (Ki67), apoptosis (TUNEL), and angiogenesis (MVD) in tumor samples obtained at necropsy. Results: In vitro cytotoxicity assays revealed similar effects (IC50=20-60 nM) of maximum tolerated dosing (MTD) and metronomic dosing of ABP on HeyA8 tumor cells (p<0.05). In vivo therapy experiments using the SKOV3ip1 and HeyA8 tumor models demonstrated that treatment with metronomic ABP alone and in combination with metronomic topotecan resulted in significant reductions in tumor weight, 62% and 96% respectively as compared to controls (p<0.01). Combination treatment with metronomically dosed ABP and topotecan further reduced tumor growth by 82% compared to topotecan alone (p<0.01). In the chemoresistant tumor model, HeyA8-MDR, metronomically dosed monotherapy with either cytotoxic agent had a modest effect on tumor growth however, combination therapy decreased tumor burden by 74% when compared to controls (p<0.01). Metronomic ABP monotherapy resulted in reduced cell proliferation (p<0.001), reduced tumor angiogenesis (p≤0.01), and increased apoptosis (p<0.01). Conclusions: Metronomically-dosed albumin-bound paclitaxel and topotecan offer a highly effective and novel therapeutic approach in ovarian carcinoma that merits further clinical development. Citation Format: Ashley N. Davis, Yvonne G. Lin-Liu, Rebecca A. Previs, Heather J. Dalton, Behrouz Zand, Justin Bottsford-Miller, Robert Coleman, Anil K. Sood. Metronomic albumin-bound paclitaxel and topotecan has potent antitumor activity in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2995. doi:10.1158/1538-7445.AM2014-2995

A phase II single-arm study of pazopanib and paclitaxel as first-line treatment for patients with advanced melanoma.

9036 Background: We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable sta...

Synergistic antitumor effect of combining metronomic chemotherapy with adoptive cell immunotherapy in nude mice

Adoptive cell immunotherapy with cytokine-induced killer cell (CIK cell) represents a promising non-toxic anticancer therapy. However, the clinical efficacy of CIK cells is limited because of abnormal tumor vasculature. Metronomic chemotherapy shows promising anticancer activity by its potential antiangiogenic effect and reduced toxicity. We hypothesized that metronomic chemotherapy with paclitaxel could improve the antitumor effect of adoptive CIK cell immunotherapy. Mice health status was analyzed by measuring mice weight and observing mice behavior. Immunohistochemistry was used to investigate the recruitment of CIK cells, the expression of endothelial cell molecules, as well as the hypoxic tumor area. Metronomic paclitaxel synergized with adoptive CIK cell immunotherapy to inhibit the growth of non-small cell lung cancer (NSCLC). Metronomic paclitaxel reduced hypoxic tumor area and increased CIK cell infiltration. Hypoxia impeded the adhesion of CIK cells and reduced the expression of endothelial cell adhesion molecules. In vivo studies demonstrated that more CIK cells were found in endothelial cell adhesion molecules high expressed area. Our study provides a new rationale for combining metronomic chemotherapy with adoptive cell immunotherapy in the treatment of xenograft NSCLC tumors in immunodeficient mice. Further clinical trials integrating translational research are necessary to better evaluate the clinical benefit of this promising approach.

Updated interim analysis of UCI 09-53: A phase II, single arm study of pazopanib and paclitaxel as first-line treatment for subjects with unresectable advanced melanoma.

9082 Background: Metastatic melanoma lacks effective therapy. Pazopanib is an inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has antiangiogenic activity in renal cell cancer as well as inhibition of melanoma tumor xenografts. We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax design, with a planned interim analysis to confirm >3 responders to move to the second stage. To date, 31 patients are evaluable for response. All subjects were treatment naïve and received paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and pazopanib 800mg continuous daily oral dose. The primary endpoint is 6 month progression free survival. Exploratory endpoints include biomarker analysis that may be associated with treatment outcomes (serum VEGF, soluble VEGFR-2, serum HIF, serum TSP1 and BRAF mutation status). An additional exploratory endpoint includes the in vitro activity of pazopanib and paclitaxel on patient biopsy material co-cultured with vascular endothelial cells. RECIST 1.1 criteria were used to define treatment response (SD criteria was a minimum interval of 8 weeks). Results: For the 31 evaluable patients treated to date the following results were seen: 1 CR, 9 PR’s, 13 SD’s and 8 PD’s. The overall RR (CR+PR) was 32%. Total disease control rate was 74% (CR+PR+SD). The most common AEs/lab abnormalities were diarrhea (66%) nausea (60%), hypertension (63%), fatigue (63%) and vomiting (29%). Grade 3-4 AEs included hypertension (26%), transaminitis (23%) and neutropenia (17%).One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 15 patients and for paclitaxel in 4 patients. Conclusions: Updated interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 32% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients. Clinical trial information: NCT01107665.

Immunotherapy with HER-2 and VEGF peptide mimics plus metronomic paclitaxel causes superior antineoplastic effects in transplantable and transgenic mouse models of human breast cancer

HER-2 and the vascular endothelial factor receptor (VEGF) represent validated targets for the therapy of multiple tumor types and inhibitors of these receptors have gained increasing importance in the clinic. In this context, novel bioactive agents associated with better therapeutic outcomes and improved safety profile are urgently required. Specifically engineered HER-2- and VEGF-derived peptides in combination with low-dose chemotherapy might provide a substantial impact on tumor metastasis and cancer progression. We tested the antitumor effects of HER-2 and VEGF peptide mimics in combination with metronomic paclitaxel in both PyMT and Balb/c murine model challenged with TUBO cells. The combination of low-dose paclitaxel and HER-2 or VEGF peptide mimics had greater inhibitory effects than either agent alone. Peptide treatment caused virtually no cardiotoxic effects, while paclitaxel and the anti-HER-2 antibody trastuzumab (Herceptin), exerted consistent cardiotoxicity. The combination regimen also promoted significant reductions in tumor burden and prolonged survival rates in both transgenic and transplantable tumor models. Tumor weights were significantly reduced in mice treated with HER-2 peptides alone, and even more in animals that received HER-2 peptide with low-dose paclitaxel, which alone had no significant effects on tumor growth in the transgenic model. Specifically engineered native peptide sequences from HER-2 and VEGF used in combination with metronomic paclitaxel demonstrate enhanced anticancer efficacy and an encouraging safety profile. This novel approach to targeted therapy may offer new avenues for the treatment of breast cancer and other solid tumors that overexpress HER-2 and VEGF.

A phase II single arm study of pazopanib and paclitaxel as first-line treatment for unresectable stage III and stage IV melanoma: Interim analysis.

8524 Background: Metastatic melanoma lacks effective therapy. Pazopanib is a small-molecule inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has antiangiogenic activity in renal cell cancer as well as inhibition of melanoma tumor xenografts. We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax design, with a planned interim analysis to confirm >3 responders to move to the second stage. To date, 20 eligible patients have been enrolled with 17 evaluable for response. All subjects were treatment naïve and received paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and pazopanib at 800mg as a continuous daily oral dose. The primary endpoint is 6 month progression free survival. Exploratory endpoints include biomarker analysis that may be associated with treatment outcomes (serum VEGF, soluble VEGF R2, serum HIF, serum TSP1 and BRAF mutation status). An additional exploratory endpoint includes the in vitro activity of pazopanib and paclitaxel on patient biopsy material co-cultured with vascular endothelial cells. RECIST criteria were used to define treatment response. Results: For the 17 evaluable patients treated to date the following results were seen: 1 CR, 6 PR’s, 8 SD’s and 2 PD’s. The overall RR (CR+PR) was 40%. Total disease control rate was 80% (PR+SD). The most common AEs/lab abnormalities were nausea (71%), hypertension (57%), fatigue (57%) and vomiting (43%). Grade 3-4 AEs included hypertension (28%), transaminitis (21%) and neutropenia (14%). One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 5 patients and for paclitaxel in one patient. Conclusions: Planned interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 40% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients.

Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma

There is a strong rationale in the use of antiangiogenic therapy in the management of adrenocortical carcinoma (ACC). Metronomic administration of chemotherapy and antiangiogenic drugs can be synergistic in targeting endothelial cells. We assessed the activity of sorafenib plus metronomic paclitaxel as second/third-line therapy in advanced ACC patients. We also tested the activity of sorafenib and paclitaxel against NCI-H295R in vitro. Multicenter, prospective phase II trial. Setting Referral centers for ACC. Twenty-five consecutive metastatic ACC patients who progressed after mitotane plus one or two chemotherapy lines were planned to be enrolled. The patients received a combination of i.v. paclitaxel (60 mg/m(2) every week) and oral sorafenib (400 mg twice a day) till progression. The primary aim was to measure the progression-free survival rate after 4 months and the secondary aims were to assess the objective response rate and toxicity. Tumor progression was observed in nine evaluable patients at the first assessment. These results led to the premature interruption of the trial. The treatment was well tolerated. The most relevant toxicities were fatigue, being grade 2 or 3 in four patients, and hypophosphatemia, being grade 3 in three patients. In the in vitro study, sorafenib impaired the viability of H295R cells with dose-response and time-response relationships. The in vitro sorafenib activity was not increased in combination with paclitaxel. Despite the in vitro activity, sorafenib plus weekly paclitaxel is an inactive salvage treatment in patients with advanced ACC and should not be recommended.

Metronomic Chemotherapy Enhances Antitumor Effects of Cancer Vaccine by Depleting Regulatory T Lymphocytes and Inhibiting Tumor Angiogenesis

Although cancer vaccines are emerging as innovative methods for cancer treatment, these alone have limited potential for treating measurable tumor burden. Thus, the importance of identifying anticancer strategies with greater potency is necessary. The chimeric DNA vaccine CTGF/E7 (connective tissue growth factor linked to the tumor antigen human papillomavirus 16 E7) generates potent E7-specific immunity and antitumor effects. We tested immune-modulating doses of chemotherapy in combination with the CTGF/E7 DNA vaccine to treat existing tumors in mice. Metronomic low doses of paclitaxel, not the maximal tolerable dose, are synergistic with the antigen-specific DNA vaccine. Paclitaxel, given in metronomic sequence with the CTGF/E7 DNA vaccine enhanced the vaccine's potential to delay tumor growth and decreased metastatic tumors in vivo better than the CTGF/E7 DNA vaccine alone. The two possible mechanisms of metronomic paclitaxel chemotherapy are the depletion of regulatory T cells and the inhibition of tumor angiogenesis rather than direct cancer cell cytolytic effects. Results indicate that combination treatment of metronomic chemotherapy and antigen-specific DNA vaccine can induce more potent antigen-specific immune responses and antitumor effects. This provides an immunologic basis for further testing in cancer patients.

Alternative dosing schedules and administration updates for Ixabepilone

Ixabepilone 40 mg/m(2) (every 3 weeks) is approved for use in metastatic breast cancer as monotherapy as early as third line and in combination with capecitabine as early as first line in tumors that are resistant or refractory to anthracyclines and taxanes. This article seeks to familiarize oncology pharmacists with the options at their disposal to aid in management of ixabepilone therapy. Toxicity with ixabepilone is reversible and responsive to dose reduction or delay, and the 40 mg/m(2) dose may be reduced to 32 mg/m(2) and subsequently to 25 mg/m(2) should toxicities arise. However, available clinical data cannot support beginning ixabepilone therapy at a reduced dose to mitigate toxicity. Because ixabepilone's mechanism of action and adverse event profile resemble those of the taxanes, it has been postulated that weekly administration of ixabepilone (15-20 mg/m(2) weekly for 3 weeks with a 1 week break) may provide similar advantages to those seen with weekly metronomic paclitaxel administration. Within the last year, preliminary data has emerged that begins to answer questions regarding the use of weekly ixabepilone. The regimen appears to be effective and well-tolerated in metastatic breast cancer and other tumor types, although data from definitive head-to-head studies with the approved regimen are not yet available. Moreover, a recent label change now incorporates alternative infusion liquids to Lactated Ringer's Solution into the approved dilution protocol for ixabepilone, and similarities and differences from taxane administration are discussed. It is hoped that the influx of new data regarding dosing, scheduling, and administration options for ixabepilone will continue to increase the pharmacist's ability to optimize treatment outcomes for breast cancer patients.

Low-dose metronomic chemotherapy of paclitaxel synergizes with cetuximab to suppress human colon cancer xenografts

Low-dose metronomic (LDM) chemotherapy represents a new strategy to treat solid tumors by stronger antiangiogenic activity and lower side effects, especially in combination with other antiangiogenic agents. This study aims to investigate whether LDM chemotherapy of paclitaxel could synergize with cetuximab, an antiangiogenic agent to suppress HT-29 human colon tumors in BALB/c nude mice. To explore its possible mechanism, the tumor vascular status was detected by staining with anti-CD31 Ab and the tumoral expression of thrombospondin-1 was examined by immunohistochemistry, western blot analysis, and real-time PCR. Our results showed that empirical metronomic paclitaxel regimens in combination with cetuximab induces significant and durable antitumor responses without overt toxicity. Paclitaxel LDM chemotherapy displayed stronger antiangiogenic activity than maximum tolerable dose (MTD) chemotherapy, whereas MTD chemotherapy induced more apoptotic cells. The combinational therapy with LDM and cetuximab showed the strongest antiangiogenic activity among all the groups. Paclitaxel LDM chemotherapy also dramatically upregulated the expression of thrombospondin-1, but MTD chemotherapy did not. These results suggest that the combination of paclitaxel LDM chemotherapy and cetuximab represents a potent strategy to combat colon cancers.

Synthesis and characterization of a micellar drug carrier for the metronomic delivery of paclitaxel

Environmentally sensitive carriers have been designed for metronomic Paclitaxel (PAX) delivery to tumors. PAX has been successfully conjugated to a diblock copolymer using different chemically labile hydrozone linkers to control its release rate under low pH conditions. These diblock copolymers are being characterized using NMR to determine the degree and location of substitution. These carriers are currently being evaluated to determine their potential for metronomic PAX delivery.

Serum Vascular Endothelial Growth Factor as a Predictive Factor in Metronomic (Weekly) Paclitaxel Treatment for Advanced Head and Neck Cancer

To evaluate serum vascular endothelial growth factor (VEGF) as a prognostic factor in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck treated with metronomic (weekly) paclitaxel. Before-and-after trial. A total of 33 consecutive patients were enrolled. Patients with recurrent and/or metastatic cancer of the head and neck refractory to platinum-based chemotherapy met inclusion criteria. Tertiary referral center. Patients were treated weekly with 80 mg/m(2) of paclitaxel for 6 weeks. Blood samples were collected after each dose and analyzed for serum VEGF using enzyme-linked immunosorbent assay kits. Nonparametric tests were used to analyze serum VEGF levels. In 33 patients, complete response was achieved in 1 (3%) and partial response in 20 (61%). No differences were found between responders and nonresponders with different levels of serum VEGF at any of the measurement times (baseline, after the first dose, and after the sixth dose). In responders, the median level of serum VEGF decreased after the first dose compared with baseline, but by the sixth dose, the median serum VEGF level had returned to baseline levels in all groups. The intensity of the serum VEGF level decrease (simple decrease, a decrease of at least 30%, or a decrease of at least 70%) was not related to response. The progression-to-disease time increased in the patients with a serum VEGF level reduction of at least 30% (P = .01) after 6 doses and decreased in patients with initially high levels, which remained high after the sixth dose (P = .03). Serum VEGF levels after the first dose of paclitaxel may predict response to weekly paclitaxel in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Initially high serum VEGF levels that persist after the sixth dose predict a shorter period until tumor progression.

Weekly carboplatin and nab-paclitaxel plus trastuzumab, or plus or minus bevacizumab: Clinical response in patients with breast cancer

10699 Background: We previously reported a high, complete pathological remission rate in the neoadjuvant setting using carboplatin and metronomic paclitaxel plus or minus trastuzumab (TC ± H) following anthracycline therapy in patients with HER2+ and triple negative (ER-, PR- and HER2-) breast cancer, respectively. [SABCS 2004 abstract #1110 & SABCS 2005 # 5056] . We now report the clinical outcome of patients with breast cancer who were treated with carboplatin and a 130-nm, albumin-bound form of paclitaxel (nab-paclitaxel) plus trastuzumab (nab-TCH) in HER2+ patients, or plus or minus bevacizumab (nab-TC ± B) in HER2- patients or trastuzumab-exposed HER2+ patients. Methods: Twelve consecutive patients with performance status of 0–2 were treated in the neoadjuvant or metastatic setting from April 2005 to December 2005. Of the 12 patients, 10 received prior anthracycline therapy, 10 received prior taxane therapy, 4 received prior carboplatin therapy, and 4 received prior trastuzumab therapy. Patients received carboplatin calculated at an area under the concentration-time curve (AUC) of 2 and nab-paclitaxel at 80–100 mg/m2 weekly for 3 weeks followed by 1 week of rest. Either concurrent trastuzumab therapy was administered at 4 mg/kg loading dose, followed by maintenance dose of 2 mg/kg/wk (3 patients) or concurrent bevacizumab therapy was administered at 10mg/kg every 2 weeks (8 patients). One patient received carboplatin and nab-paclitaxel alone. Results: At this point, 9 pts are evaluable. Eight of the first 9 patients achieved a major clinical response (89%, 95% CI: 52%−100%), with 2 of the 8 responders obtaining a documented complete clinical response. Of the 3 remaining patients, 1 had clinical resolution of malignant ascites, 1 had normalization of tumor marker, and 1 had resolution of pain at early follow up. None of the patients had neutropenic fever or grade 3/4 neuropathy or arthralgia. Conclusions: The above combinations (nab-TCH or nab-TC ± B demonstrated promising antitumor activity in patients with breast cancer in the neoadjuvant and metastatic breast cancer. We have initiated a phase II study exploring nab-TCH and nab-TCB (sequenced after doxorubicin and cyclophosphamide) in the neoadjuvant setting. [Table: see text]

Antiangiogenic effect of metronomic paclitaxel treatment in prostate cancer and non-tumor tissue in the same animals: a quantitative study.

Well-tolerated continuous or metronomic chemotherapy can exert a marked antiangiogenic and thus superior antitumor effect compared with conventional high-dose, temporarily spaced-out chemotherapy, as shown in preclinical studies. There is, however, no means of directly assessing the antiangiogenic effect in a tumor, a serious impediment to assessing the effects of putative antiangiogenic chemotherapeutics or treatments. In an attempt to circumvent or minimize this impediment we studied the antiangiogenic effect of well-tolerated metronomic paclitaxel therapy in a surrogate tumor-free tissue that allows true quantitative analysis as well as in syngeneic At-1 prostate cancer in the same rat. This novel model allows an accurate comparison of the angiogenesis-modulating effect of chemotherapy in the two tissues to be made. The effect of chemotherapy on VEGF-A-mediated angiogenesis, a characteristic of most tumors, was assessed truly quantitatively by microscopic morphometry and image analysis in the tumor-free mesentery. The chemotherapy significantly suppressed VEGF-A-mediated angiogenesis in the mesentery to an extent that closely mirrored the significant increase in tumor necrosis measured morphometrically and the significant decrease in tumor growth rate. This finding opens an avenue to study quantitatively and systematically the antiangiogenic effect of chemotherapeutic modalities and treatments that approximately mirror their antiangiogenic effect in the At-1 tumor.