Metronomic Combination Chemotherapy Research Articles

Abstract PR03: CSF-1R antibody targeting therapy with combined metronomic chemotherapy and immune checkpoint blockade enhance a B and T cell response to attenuate metastatic triple negative breast cancer

Abstract Background: Increased macrophage infiltration and elevated levels of Epithelial to Mesenchymal Transition (EMT) gene signatures are associated with a poor outcome following neo-adjuvant chemotherapy in patients with triple negative breast cancer (TNBC). Further, metastatic disease with overall the poorest survival rates has a cold tumor immune microenvironment (TIME), especially in lung and liver metastases. Interestingly, an abundance of macrophages are observed at these metastatic sites. We have extensively characterized multiple preclinical syngeneic Trp53-/- tumor models that have extensive Tumor Associated Macrophage (TAM) infiltration. These tumor models transcriptionally resemble “claudin-low”, “basal-like” and “luminal-like” breast cancers. From these models the “claudin-low” closely phenocopy the high EMT/TAM subtype observed in patients. Objective: Accordingly, we asked if SNDX-ms6352 a novel specific, high affinity monoclonal antibody targeting CSF-1R in combination with Chemotherapy (CTX) and immune checkpoint blockade might provide an alternative approach for treating established lung and liver metastases. Methods: Single cells from primary T12 mammary tumors were introduced either via tail vein injection to obtain lung metastases or portal vein (PV) injection for liver metastases. Mice were injected with BrdU and multiple lung and liver tissues are harvested randomly to identify established metastases. The mice were randomized into treatment groups and administered four weekly treatments of IgG, CTX, SNDX-ms6352, CTX+SNDX-ms6352 or CTX+SNDX-ms6352+aPD1. Tissues were harvested and fixed overnight in 4% PFA then placed in 70% EtOH for paraffin embedding and stained for H&E, Immunohistochemistry (IHC), Immunofluorescence (IF) and Imaging Mass Cytometry (IMC). Results: Following four weekly treatments of IgG, SNDX-ms6352 and CTX+/-SNDX-ms6352 we observed a decrease in lung metastatic burden and an increase in overall survival as compared to IgG, CTX and SNDX-ms6352 alone. Interestingly we also observed increased CD8 T-cell infiltration, but only in the combination treated mice 28 and 56 days post treatment. However, lung metastases recurred in all of the mice several weeks later. Data from IMC showed intra-tumoral heterogeneity with increased PD-L1 and Ki67. Short term treated lung and liver metastases with the addition of aPD1 demonstrated increased CD20+ B and CD8+ T cell expansion and cleared most of the lung and liver metastatic burden. These results suggest that targeting macrophages enhances the immunostimulatory effect of metronomic CTX with immune checkpoint blockade in treating not only primary tumors, but also established lung and liver metastases via the activation of the tumor immune microenvironment. Supported by R01CA148761-12 and American Cancer Society – AutoZone Breast Cancer Postdoctoral Fellowship, PF-22-163-01-MM grants. Citation Format: Diego A Pedroza, Qian Zhu, Weigou Wu, Paul Porter, Xiang H-F Zhang, Jeffrey M Rosen. CSF-1R antibody targeting therapy with combined metronomic chemotherapy and immune checkpoint blockade enhance a B and T cell response to attenuate metastatic triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR03.

Dual‑directional effect of vinorelbine combined with cisplatin or fluorouracil on tumor growth and metastasis in metronomic chemotherapy in breast cancer

Dual‑directional effect of vinorelbine combined with cisplatin or fluorouracil on tumor growth and metastasis in metronomic chemotherapy in breast cancer

Dose-dependent bidirectional pharmacological effects of vinorelbine-based metronomic combination chemotherapy on tumor growth and metastasis and mechanisms in melanoma mouse model.

There is evidence that the empirical setting of doses and schedules of antineoplastic agents in metronomic chemotherapy (MC) might lead to undesirable outcomes, such as promoting tumor growth or metastasis at certain low doses. However, details about the dose effect of antineoplastic agents in MC have not been fully known yet. Vinorelbine combined with cisplatin or fluorouracil (VNR/CDDP or VNR/FU) was selected to investigate its effects on tumor growth or metastasis as well as mechanisms. Experimental techniques, including immunohistochemistry, western blot, immunofluorescence, and flow cytometry, were used to explore the mechanisms, along with cell proliferation, apoptosis, migration, and invasion. The results showed that VNR/CDDP or VNR/FU promoted tumor growth and metastasis at low doses and inhibited them at high ones. Except that expressions of apoptotic proteins were elevated at both low and high doses, low-dose treatments enhanced angiogenesis and promoted the mobilization and recruitment of myeloid-derived suppressor cells (MDSCs), while high-dose treatments reversed these effects. Additionally, low concentrations of VNR/CDDP or VNR/FU stimulated tumor cell functions such as anti-apoptosis, migration, and invasion, but high concentrations only suppressed cell proliferation and increased apoptosis. This study elucidated a bidirectional action mode regulated by multiple mechanisms at different doses in MC and also highlighted the risks of low-dose metronomic administration of antineoplastic agents in the clinic. More preclinical and clinical studies focusing on the dose-effect of metronomic regimens are urgently needed because an effective therapeutic regimen should be an optimal setting of drugs, doses, schedules, or combinations.

<p>Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative</p>

ObjectiveThe rational combination of immunotherapy with standard chemotherapy shows synergistic clinical activities in cancer treatment. In the present study, an oral powder formulation of pemetrexed (PMX) was developed to enhance intestinal membrane permeability and investigate its application in metronomic chemotherapy in combination with immunotherapy.MethodsPMX was ionically complexed with a bile acid derivative (Nα-deoxycholyl-l-lysyl-methylester; DCK) as a permeation enhancer and mixed with dispersing agents, such as poloxamer 188 (P188) and Labrasol, to form an amorphous oral powder formulation of PMX/DCK (PMX/DCK-OP).ResultsThe apparent permeability (Papp) of PMX/DCK-OP across a Caco-2 cell monolayer was 2.46- and 8.26-fold greater than that of PMX/DCK and free PMX, respectively, which may have been due to the specific interaction of DCK with bile acid transporters, as well as the alteration of membrane fluidity due to Labrasol and P188. Furthermore, inhibition of bile acid transporters by actinomycin D in Caco-2 cell monolayers decreased the Papp of PMX/DCK-OP by 75.4%, suggesting a predominant role of bile acid transporters in the intestinal absorption of PMX/DCK-OP. In addition, caveola/lipid raft-dependent endocytosis, macropinocytosis, passive diffusion, and paracellular transport mechanisms significantly influenced the permeation of PMX/DCK-OP through the intestinal membrane. Therefore, the oral bioavailability of PMX/DCK-OP in rats was 19.8%±6.93%, which was 294% higher than that of oral PMX. Moreover, an in vivo anticancer efficacy study in B16F10 cell-bearing mice treated with a combination of oral PMX/DCK-OP and intraperitoneal anti-PD1 exhibited significant suppression of tumor growth, and the tumor volume was maximally inhibited by 2.03- and 3.16-fold compared to the oral PMX/DCK-OP and control groups, respectively.ConclusionThese findings indicated the therapeutic potential of a combination of low-dose oral chemotherapy and immunotherapy for synergistic anticancer efficacy.

Metronomic combination chemotherapy using everolimus and etoposide for the treatment of non‐Hodgkin lymphoma

Patients with Non‐Hodgkin lymphoma (NHL) treated by conventional chemotherapeutic drugs usually require a long recovery period. However, metronomic combination chemotherapy (MCC) enhances therapeutic efficacy and decreases side effects in the treatment of NHL. In this study, we tested and compared the effects of metronomic chemotherapy (MC) using podophyllotoxin derivative etoposide (VP‐16) alone and that of MCC using both VP‐16 and everolimus (RAD001) in the treatment of NHL. Two types of NHL cells, OCI‐LY‐10 and SU‐DHL‐6, were employed for the experiments. Cell proliferation, apoptosis, and cell senescence were measured to test the effects of drugs in each experiment. In addition, the influences of MC and MCC on the cell cycle and autophagy pathway were evaluated to study the functional mechanisms behind their effects. Finally, we conducted analyses of the growth inhibitory effect and synergistic activity for different MCC. The results showed that MC using low‐dose VP‐16 alone demonstrated strong treatment effects in terms of inducing apoptosis, cell senescence, and reducing tumor cell proliferation, and this treatment also led to changes of the cell cycle. Compared with MC, MCC using VP‐16 and RAD001 together demonstrated even stronger treatment effects, with both the cell cycle and autophagy‐related proteins being affected. Considering the synergistic activity, our results showed the MCC of VP‐16 48 hours + RAD001 24 hours is the optimal method for treating NHL.

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.

Pilot phase II study of metronomic chemotherapy in combination with bevacizumab in patients with advanced non-squamous non-small cell lung cancer

IntroductionThe goal of this study was to explore the efficacy and tolerability of metronomic chemotherapy, a novel anti-angiogenic treatment strategy, in combination with bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). MethodsSubjects with newly diagnosed stage IV NSCLC were treated with 4-week cycles of paclitaxel 80mg/m2 and gemcitabine 300mg/m2 weekly for three weeks, plus bevacizumab 10mg/kg every two weeks. Radiologic assessments were performed every 8 weeks. The primary endpoint was progression free survival (PFS). An exploratory objective was to correlate plasma levels of angiogenic biomarkers with treatment response. ResultsThirty-nine subjects were included in the intent to treat (ITT) analysis. The objective response rate (ORR) was 56%, the median PFS was 8.5 months, and median overall survival (OS) was 25.5 months. The PFS rate at 6, 12, and 24 months was 61%, 21%, and 11% respectively. The OS rate at 12 and 24 months was 74% and 53% respectively. Treatment was well tolerated, without significant myelosuppressive, gastrointestinal, or neurologic events. Subjects with less than median baseline values of angiopoietin-2 and IL-8 experienced significantly longer PFS. Longer OS was associated with subjects with less than the median baseline values for PLGF and angiopoietin-2. There were statistically significant differences in median values of several biomarkers between cycles 1 and 3 in subjects with objective responses. ConclusionsThe combination of paclitaxel and gemcitabine, delivered in a metronomic schedule, in combination with bevacizumab, appears to be an effective and tolerable treatment strategy in patients with advanced NSCLC.

Metronomic chemotherapy with 5-fluorouracil and cisplatin for inoperable malignant bowel obstruction because of peritoneal dissemination from gastric cancer.

Gastric cancer is the 2nd leading cause of cancer death worldwide. Malignant bowel obstruction (mbo) is a common complication in advanced gastric cancer because of peritoneal dissemination. A multicentre prospective study reported that patients with peritoneal dissemination of gastric origin survive for a median of 3.1 months. The aim of the present study was therefore to evaluate the efficacy and safety of metronomic combination chemotherapy with 5-fluorouracil and cisplatin in inoperable mbo from peritoneal dissemination in gastric cancer. Gastric cancer patients diagnosed with inoperable mbo because of peritoneal dissemination were treated with infusional 5-fluorouracil 300 mg/m(2) daily on days 1-5 and 8-12, and cisplatin 5 mg/m(2) daily on days 1-4 and 8-11 every 3 weeks. The primary endpoint was symptom control (remission of obstruction); the secondary endpoint was symptom control time and survival; the tertiary endpoint was adverse effects. Between January 2013 and December 2014, 26 patients received the study treatment. Before treatment, 18 patients (69.2%) were nil per os, and 8 (30.8%) could consume liquids. After a mean of 3.3 cycles of the study treatment, just 4 patients (15.4%) was still nil per os. Of the remaining 22 patients, 3 (11.5%) could consume liquids, 7 (26.9%) could consume soft solids, and 12 (46.2%) ate a full diet. The improved ability to eat was statistically significant (p < 0.0001). Median duration of remission from mbo was 105 days. Median survival was 182 days. The 3-month survival rate was 69.2%, and the 6-month survival rate was 53.8%. Treatment was well tolerated, with grade iii toxicities consisting of thrombocytopenia in 1 patient (3.84%) and mucositis in 2 patients (7.7%). No abnormalities in serum creatinine were observed. Metronomic combination chemotherapy with 5-fluorouracil and cisplatin is well tolerated and shows activity in inoperable mbo because of peritoneal dissemination in gastric cancer. Metronomic combination chemotherapy with 5-fluorouracil and cisplatin provides a rationale for exploring this medical problem in the future.

An in vitro assessment of liposomal topotecan simulating metronomic chemotherapy in combination with radiation in tumor-endothelial spheroids.

Low dose metronomic chemotherapy (LDMC) refers to prolonged administration of low dose chemotherapy designed to minimize toxicity and target the tumor endothelium, causing tumor growth inhibition. Topotecan (TPT) when administered at its maximum tolerated dose (MTD) is often associated with systemic hematological toxicities. Liposomal encapsulation of TPT enhances efficacy by shielding it from systemic clearance, allowing greater uptake and extended tissue exposure in tumors. Extended release of TPT from liposomal formulations also has the potential to mimic metronomic therapies with fewer treatments. Here we investigate potential toxicities of equivalent doses of free and actively loaded liposomal TPT (LTPT) and compare them to a fractionated low dose regimen of free TPT in tumor-endothelial spheroids (TES) with/without radiation exposure for a prolonged period of 10 days. Using confocal microscopy, TPT fluorescence was monitored to determine the accumulation of drug within TES. These studies showed TES, being more reflective of the in vivo tumor microenvironment, were more sensitive to LTPT in comparison to free TPT with radiation. More importantly, the response of TES to low-dose metronomic TPT with radiation was comparable to similar treatment with LTPT. This TES study suggests nanoparticle formulations designed for extended release of drug can simulate LDMC in vivo.

Abstract 2060: Metronomic chemotherapy (MCT): comparison of the efficacy of two combinations of drugs for the treatment of murine mammary adenocarcinomas.

Abstract Metronomic chemotherapy (MCT) refers to the chronic, equally spaced, delivery of low doses of different chemotherapeutic drugs, without extended interruptions. We have developed two combined MCT schemes for the treatment of mammary tumors: A) cyclophosphamide (Cy) 30 mg/kg/day p.o. + celecoxib (Cel) 30 mg/kg p.o. 5 times/week, and B) Cy 20 mg/kg/day p.o. + doxorubicin (Dox) 0.5 mg/kg, 3 times/week i.p. They were tested in two experimental models of mammary adenocarcinomas: I) M-406 and II) M-234p syngeneic with inbred CBi and BALB/c mice, respectively. Our present aim was to compare efficacy and toxicity of MCT combined A and B treatments in both tumor-models. There were analyzed antitumor and antimetastatic effects, survival and toxicity. The % of reduction of tumor volume of animals in the treated group with respect to control group without treatment [median (range): AI: 77.9 (50.9-89.9), AII: 84.4 (30-99.4), BI: 95.6 (57-99.6), BII: 75.5 (62.5-96.8)] didn't differ between treatments or between tumor-models (non parametric ANOVA). The % of reduction of lung metastatic burden [AI: 99.8 (97.1-99.2) AII: 99.7 (98.7-100), BI: 90.6 (35.9-96.6), BII: 90 (48.4-99.3)] was significantly different among all the groups (P&amp;lt;0.01); Dunn's post-test showed differences in AII vs BII (P&amp;lt;0.05). The analysis of survival showed higher values in treated groups, being the % of survival increase with respect to controls [AI: 56.5 (4.3-56.5) AII: 77.6 (5.3-84.2), BI: 110.9 (60-308.2), BII: 36.1 (12.4-113)] did not reach statistical significance (P=0.054). The treatments toxicity, evaluated by evolution of body weight and total leucocytes count, was similar in both tumor-models and treatments. The antitumor therapeutic efficacy was comparable in both MCT schemes and so was the toxicity generated by them. The combination Cy + Cel was superior than Cy + Dox related to antimetastatic power, suggesting its potential use at the adjuvant setting. That observation, together with the advantage that represents the oral administration of the Cy + Cel drug combination, thus leading to a better quality of life for tumor bearers, points at its election for the treatment of mammary tumors with metronomic chemotherapy. Citation Format: María J. Rico, Leandro E. Mainetti, Herman A. Perroud, Viviana R. Rozados, O. Graciela Scharovsky. Metronomic chemotherapy (MCT): comparison of the efficacy of two combinations of drugs for the treatment of murine mammary adenocarcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2060. doi:10.1158/1538-7445.AM2013-2060

Safety and Therapeutic Effect of Metronomic Chemotherapy with Cyclophosphamide and Celecoxib in Advanced Breast Cancer Patients

Metronomic chemotherapy (MCT), the chronic administration, at regular intervals, of low doses of chemotherapeutic drugs without extended rest periods, allows chronic treatment with therapeutic efficacy and low toxicity. Our preclinical results suggested that combined MCT with cyclophosphamide and celecoxib could inhibit breast cancer growth. The aim of this study was to determine the toxicity, safety and efficacy of oral MCT with cyclophosphamide 50 mg per orem daily and celecoxib 400 mg (200 mg per orem two-times a day) in advanced breast cancer patients. During the first stage of the study, the therapeutic response consisted of prolonged stable disease for ≥24 weeks in six out of 15 (40%) patients with a median duration of 37.5 weeks and a partial response in one out of 15 (response rate: 6.7%) patients lasting 6 weeks. The overall clinical benefit rate was 46.7%. The median time to progression was 14 weeks. Progression-free survival at 24 weeks was 40% and the 1-year overall survival rate was 46.7%. The adverse events were mild (gastric, grade 1; and hematologic, grade 1 or 2). No grade 3 or 4 toxicities were associated with the treatment. Evaluation of patients' quality of life showed no changes during the response period. MCT with cyclophosphamide plus celecoxib is safe and shows a therapeutic effect in advanced breast cancer patients.

Metronomic chemotherapy (MC) in the neoadjuvant setting: Results of two parallel feasibility trials in patients (pts) with HER2 positive (HER2+) and negative (HER2-) locally advanced breast cancer (LABC) (Traq-Me and TAME).

197 Background: In a previous randomized trial (SWOG 0012), MC seemed to improve pCR rates compared to standard anthracycline/taxane neoadjuvant chemotherapy (NC). We aimed to evaluate the feasibility of MC with a taxane→anthracycline schedule, which has also been shown potentially superior to the reverse sequence [J Clin Oncol 28:15s, 2010 (suppl; abstr 548)]. We also aimed to establish the feasibility of MC in combination with trastuzumab. Methods: The original accrual goal was 25 HER2+ pts and 40 HER2- pts. HER2- pts received MC consisting of paclitaxel (100mg/m2) x8 weeks followed by doxorubicin (24mg/m2) x9 weeks combined with oral cyclophosphamide (100mg/day), without G-CSF. HER2+ pts also received trastuzumab (4 mg/kg followed by 2mg/kg) concurrently with the entire CT. Objectives: Primary: To evaluate the feasibility of these schedules (defined as a febrile neutropenia [FN] rate no higher than 10%). Secondary: cardiac safety and general tolerability; efficacy as measured by objective clinical, radiological and pathologic complete response (pCR). Results: Almost all pts were staged as III (TraQme 8/9 88% and MeTo 4/11 36%). The HER2+ cohort was prematurely closed after 2 (22%) pts developed G3 pneumonitis (during the metromonic phase). Both responded to medical treatment and recovered. One pt had G2 hand-foot skin reaction (HFS) and another had G2 mucositis. The HER2- cohort was also prematurely closed with only 11 pts because of high rates of mucocutaneous toxicity (G3 HFS in 36%, G3 rash in 9%) and also due to the recent SWOG0221 negative results. There were 2 (18%) cases of FN and 3 (27%) of G4 neutropenia in this cohort, but no cases of pneumonitis. 1/11(9%) HER2- and 5/9HER2+(55%) pts had a pCR. VEGF pathway-related biomarkers were collected and will be presented at a later date. Conclusions: The proposed MC schedules proved too toxic to be considered for further clinical development. In addition, MC resulted in unexpectedly high rates of severe pulmonary toxicity when given in combination with trastuzumab. HER2+ but not HER2- pts had an impressively high pCR rate.

Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo.

Several chemotherapeutic drugs have immune-modulating effects. For example, cyclophosphamide (CP) and gemcitabine (GEM) diminish immunosuppression by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), respectively. Here, we show that intermittent (metronomic) chemotherapy with low-dose CP plus GEM can induce anti-tumor T cell immunity in CT26 colon carcinoma-bearing mice. Although no significant growth suppression was observed by injections of CP (100 mg/kg) at 8-day intervals or those of CP (50 mg/kg) at 4-day intervals, CP injection (100 mg/kg) increased the frequency of tumor peptide-specific T lymphocytes in draining lymph nodes, which was abolished by two injections of CP (50 mg/kg) at a 4-day interval. Alternatively, injection of GEM (50 mg/kg) was superior to that of GEM (100 mg/kg) in suppressing tumor growth in vivo, despite the smaller dose. When CT26-bearing mice were treated with low-dose (50 mg/kg) CP plus (50 mg/kg) GEM at 8-day intervals, tumor growth was suppressed without impairing T cell function; the effect was mainly T cell dependent. The metronomic combination chemotherapy cured one-third of CT26-bearing mice that acquired tumor-specific T cell immunity. The combination therapy decreased Foxp3 and arginase-1 mRNA levels but increased IFN-γ mRNA expression in tumor tissues. The percentages of tumor-infiltrating CD45(+) cells, especially Gr-1(high) CD11b(+) MDSCs, were decreased. These results indicate that metronomic chemotherapy with low-dose CP plus GEM is a promising protocol to mitigate totally Treg- and MDSC-mediated immunosuppression and elicit anti-tumor T cell immunity in vivo.

Metronomic chemotherapy in combination with antiangiogenic treatment induces mosaic vascular reduction and tumor growth inhibition in hepatocellular carcinoma xenografts

In addition to sprouting angiogenesis, other mechanisms, such as mosaic tumor vessel formation, have been recognized to contribute to tumor vascularization. We sought to examine vascular alteration as well as tumor growth inhibition after treatment with antiangiogenic therapy, chemotherapy alone or in combination. Hepatocellular carcinoma cells (Hep3B) expressed green fluorescent protein were utilized to establish orthotopic xenograft model in nude mice. The formation and distribution of mosaic vessels was analyzed quantitatively by immunolabeling. Next, changes in tumor microcirculation and therapeutic effects on tumor growth were evaluated in several different treatment groups: control, conventional doxorubicin, metronomic doxorubicin, bevacizumab, bevacizumab plus conventional doxorubicin, and bevacizumab plus metronomic doxorubicin. In addition, we examined the effects of combined regimens on lung metastasis using a highly metastatic human hepatocellular carcinoma (HCCLM3) mouse model. Approximately 62 % of the vessels were present in the central part or near the midsection of the tumor and were mosaic. Only the combined antiangiogenic treatment and chemotherapy (metronomic schedule, P = 0.00; conventional schedule, P = 0.02) had a significant effect on the degree of mosaic vasculature. Metronomic doxorubicin in combination with bevacizumab had an even more profound effect than bevacizumab plus conventional doxorubicin (P < 0.05) on tumor growth inhibition and survival. However, bevacizumab plus metronomic doxorubicin failed to inhibit lung metastasis compared with antiangiogenic monotherapy. Metronomic chemotherapy in combination with antiangiogenic treatment results in the reduction of mosaic tumor vasculature, inhibition of tumor growth, and enhanced survival of mice. Further investigation of drug scheduling is required to optimize antitumor activity.

Metronomic chemotherapy (MC): Results of two feasibility trials in patients (pts) with HER2 positive (HER2+) and negative (HER2-) locally advanced breast cancer (LABC).

e11513 Background: In SWOG0012, MC improved pathologic complete response (pCR) compared to standard neoadjuvant chemotherapy (NC). We evaluated the feasibility of MC with a taxane→anthracycline schedule, which has also been shown potentially superior to the inverse sequence. We also evaluated the feasibility of MC in combination with trastuzumab. Methods: The primary objective was feasibility (defined as a febrile neutropenia (FN) rate ≤10%). Secondary objectives were cardiac safety, tolerability and efficacy as measured by objective response and pCR. The original accrual goal was 25 Her2+ pts and 40 Her2- pts. Her2- pts received paclitaxel (100mg/m2) x8 weeks followed by doxorubicin (24mg/m2) x9 weeks combined with oral cyclophosphamide (100mg/day), without G-CSF. Her2+ pts also received weekly trastuzumab (4 mg/kg followed by 2mg/kg) concurrently with the entire CT. Results: Most pts were stage III (Her+: 8/9; Her-: 4/11). The Her2+ cohort was prematurely closed after 2(22%) pts developed G3 pneumonitis (both during the MC phase). Both recovered completely. There was 1 case of asymptomatic LVEF drop to below 50% (during the taxane phase); 1 pt had G2 hand-foot skin reaction (HFS) and another had G2 mucositis. The Her2- cohort was also prematurely closed with only 11 pts due to high rates of mucocutaneous toxicity (G3 HFS in 36%, G3 rash in 9%) and also because of SWOG0221 negative results. There were 2(18%) cases of FN, but no cases of pneumonitis. 1/11(9%) Her2- and 5/9(55%) Her2 + pts had a pCR. VEGF-related biomarkers were collected and will be presented at a later date. Conclusions: The proposed MC schedules proved too toxic to be considered for further clinical development. In addition, MC resulted in unexpectedly high rates of severe pulmonary toxicity when given in combination with trastuzumab. Her2+ but not Her2- pts had an impressively high pCR rate.

Metronomic Chemotherapy Combined With Bevacizumab and Erlotinib in Patients With Metastatic HER2-Negative Breast Cancer: Clinical and Biological Activity

BackgroundThe object of this study was to evaluate the safety and efficacy of metronomic chemotherapy in combination with bevacizumab and erlotinib in patients with HER2-negative (HER2−) metastatic breast cancer (MBC) and poor hormone receptor expression. Patients and MethodsPatients with untreated MBC were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (15 mg/kg every 3 weeks) and erlotinib (100 mg daily). ResultsOf 24 patients assessable for response, we observed 1 complete response (CR, 4%), 14 partial responses (58%), 5 patients with stable disease greater than 9 weeks' duration (SD, 21%), and 1 patient (4%) with early progression of disease. The overall clinical benefit (CB) (CR + partial response + SD > 24 weeks) was 75% (95% confidence interval [CI], 53%-90%). Median time to progression was 43 weeks (95% CI, 21-69). Patients with low levels of circulating endothelial progenitors (CEPs) at baseline had a significantly improved progression-free survival (PFS). Toxicity was generally mild. Grade 3 toxicity included diarrhea (n = 1), thrombosis (n = 1), and hypertension (n = 2). Grade 2 adverse events included diarrhea (n = 5), hand-foot syndrome (n = 13), and hypertension (n = 4). ConclusionTreatment with metronomic chemotherapy in combination with bevacizumab and erlotinib was effective in HER2−, estrogen receptor (ER)- and progesterone receptor (PR)-poor advanced breast cancer.

Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer

Metronomic combination chemotherapy with the oral fluoropyrimidine doxifluridine/5'-deoxy-5-fluorouridine (5 -DFUR) and oral cyclophosphamide (C) showed promising efficacy in a single-arm study. The oral fluoropyrimidine capecitabine was designed to deliver 5-fluorouracil preferentially to tumors, potentially improving efficacy over doxifluridine. We conducted a phase II multicenter study to evaluate an all-oral XC combination in patients with HER2-negative metastatic breast cancer (MBC). Patients received capecitabine 828mg/m(2) twice daily with cyclophosphamide 33mg/m(2) twice daily, days 1-14 every 3weeks. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Between May 2007 and April 2009, 51 patients were enrolled and 45 were included in the efficacy analysis. The median follow-up was 18.1months. ORR was 44.4% and stable disease (≥24weeks) was achieved in 13.4%, resulting in a 57.8% clinical benefit response rate. Median PFS was 12.3months (95% confidence interval: 8.9-18.9months). Median PFS was 10.7months in triple-negative disease and 13.2months in estrogen-receptor positive, HER2-negative disease. The 1- and 2-year OS rates were 86 and 71%, respectively. Median OS has not been reached. Grade 3 adverse events comprised leukopenia (26%), neutropenia (16%), and decreased hemoglobin (2%). There was no grade 3 hand-foot syndrome. Oral XC is an effective first- or second-line therapy for MBC, demonstrating high activity in both luminal A and triple-negative disease with few severe side effects. This metronomic oral combination chemotherapy could be beneficial for the treatment of HER2-negative MBC.

Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide in patients with metastatic breast cancer: A single institution experience

Background: Metronomic combination chemotherapy with the oral capecitabine (X) combined with oral cyclophosphamide (C) has showed promising efficacy without significant toxicity in three phase II studies. We widely used this XC regimen for the patients with metastatic breast cancer (MBC) in our institution by two reasons. First, the patients prefer oral, home-based therapy to IV hospital-based therapy. Second, there is an established scientific rationale for XC regimen. Capecitabine is converted to 5-FU in the presence of thymidine phosphorylase (TP).

6586 POSTER Metronomic Combination Chemotherapy With S-1 and Biweekly Paclitaxel for Advanced Gastric Cancer

6586 POSTER Metronomic Combination Chemotherapy With S-1 and Biweekly Paclitaxel for Advanced Gastric Cancer

Clinical outcome of triple-negative breast cancer with BRCA mutation in the context of dose-dense and or metronomic chemotherapy.

1109 Background: Patients with triple negative (TN) breast cancer have a high risk of early relapse and death, but have promising outcomes with dose-dense and or metronomic combination chemotherapy in BRCA-unselected cohort (rsmehta JCO 2008). With the TN breast cancer, emerging data suggests that patients with BRCA mutations treated with chemotherapy have similar outcomes as sporadic TN breast cancer. Methods: Retrospective review of 88 patients with stage I to IIIB TN breast cancer who were treated with adjuvant or neoadjuvant chemotherapy was performed. Fifteen patients (18%) were found to have BRCA mutation (12 with BRCA1 and 3 with BRCA2 mutation) while 69 patients were either negative for BRCA mutation or were not tested. Patients were treated with various regimens, but could be grouped according to the receipt of dose-dense and or metronomic (DD) versus standard (Std) chemotherapy schedules. The median follow-up was 41 months (range 4-155 months). Results: Grade, histology and stage were not significantly different between carriers and noncarriers. Mean age of carriers was 39 versus 50 for noncarriers. Relapse-free-survival survival at 3 years was 100% for carriers and 70% for noncarriers (P =0.15). Overall survival at 3 years was 100% for carriers and 83% for noncarriers (P = <0.05). In addition, stage and treatment (DD vs Std) were significant in univariate analysis. Adjusting for carrier status, stage, and treatment, only stage and treatment remained significant for relapse-free and overall survival. Conclusions: Our data supports the emerging data that shows that BRCA mutation carriers with TN disease had similar survival rates to noncarriers. Dose-dense and or metronomic schedules outperformed standard chemotherapy schedules in TN breast cancer irrespective of BRCA mutation status.