Oral Metronomic Chemotherapy Research Articles

Piperlongumine for Enhancing Oral Bioavailability and Cytotoxicity of Docetaxel in Triple-Negative Breast Cancer

Very low oral bioavailability due to extensive pre-systemic metabolism and P-gp efflux has constrained the oral metronomic chemotherapy of docetaxel (DTX). There is tremendous need of compounds facilitating oral delivery of DTX. The research was aimed to investigate the effect of piperlongumine (PPL) on human liver microsomal metabolism, Caco-2 permeability, and cytotoxicity of DTX in triple-negative breast cancer cell lines. Reduction in testosterone and DTX metabolism (twofold increase in half-life) by PPL was comparable to the standard CYP3A4 inhibitor, cyclosporine A. P-gp efflux ratio of DTX across caco-2 monolayer was reduced from 2.37 to 1.52 on co-incubation with PPL. The IC50 value of DTX was reduced three to five times and combination index values in all the cell lines were below 0.6. PPL at non-cytotoxic concentration showed significant enhancement of the antimigration effect of DTX. Expression of tumor markers such as survivin, bcl2, C-myc, and cyclin D1 were downregulated to a great extent with enhanced p53 expression when treated with combination instead of individual drug. Co-treatment with PPL led to 1.68-fold enhancement in DTX bioavailability in SD rats. PPL could be a potential candidate in overcoming the obstacles associated with oral DTX delivery with synergistic anticancer activity.

A43 - Effectiveness of Bevacizumab maintenance therapy associated with metronomic chemotherapy and hormone therapy after treatment with taxanes in patients with HER-2 negative metastatic breast cancer (mBC)

Background: it is known that the continuation of Bevacizumab after therapy with taxanes is a strategy recommended in HER-2 negative metastatic breast cancer. Currently, it is not well defined yet if and which treatment bind to the anti-VEGF antibody. However, considering the undoubted antiangiogenic effect of metronomic chemotherapy, we evaluated if the triple combination Bevacizumab, hormone therapy and chemotherapy may be an option for maintenance therapy in these type of patients. Material and methods: Our study aims to evaluate the effectiveness of the association between Bevacizumab, metronomic chemotherapy and hormone therapy, by measuring the PFS, as primary endpoint and OS and RR as secondary endpoints. We enrolled 22 patients with HER2-negative mBC, who received at least six cycles of treatment with Bevacizumab + taxanes. Progression-free patients, at the suspension of the taxane, continued treatment with the antibody, combined with oral metronomic chemotherapy and hormone therapy if receptor-positive. Results: From April 2009 to January 2015 were evaluated 22 patients who received treatment with taxanes + Bevacizumab, followed by maintenance Bevacizumab, associated to Capecitabine (45.5%), Cyclophosphamide (45.5%) or Etoposide (9%) in metronomic schedule. 17 patients (77.3%) also received hormone therapy. At a median follow-up of 19 months, 5 patients have not relapsed yet. The median PFS from beginning of maintenance was 22 months (95% CI: 6.9-37.1). The median OS was 51 months (95% CI 7.1-94.9), whereas at the time of data analysis, only 10 patients have died. CR and PR were achieved/maintained in 2 (9.1%) and 5 (22.7%) patients, respectively, for an overall response rate of 31.8%; 11 (50%) women experienced SD and 4 (18.2%) patients had a PD at first control. The treatment appears to be well tolerated. Conclusions: From our study results, the continuation of Bevacizumab, combined with chemotherapy and hormone therapy, appears to improve the chance of disease control.

P-091 Oral Metronomic Chemotherapy for locally advanced, recurrent metastatic Gastric carcinoma: A Single Group, Prospective, Phase 2 study in India

Introduction: No standard treatment exists for patients with metastatic, recurrent and inoperable locally advanced gastric cancer. Taxanes, platinums and 5 fluorouracil derivatives are commonly used, but response is less than 20% with no survival benefit. We report our experience with patient for whom oral metronomic chemotherapy was effective and tolerable in the treatment of gastric cancer with dissemination

Excellent response to oral Metronomic chemotherapy in unresectable adenocarcinoma of external auditory canal.

Excellent response to oral Metronomic chemotherapy in unresectable adenocarcinoma of external auditory canal.

A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck

BackgroundCetuximab based treatment is the recommended chemotherapy for head and neck squamous cell cancers in the palliative setting. However, due to financial constraints, intravenous (IV) chemotherapy without cetuximab is commonly used in lesser developed countries. We believe that oral metronomic chemotherapy may be safer and more effective in this setting. MethodsWe conducted an open label, superiority, parallel design, randomized phase II trial comparing oral MCT [daily celecoxib (200mg twice daily) and weekly methotrexate (15mg/m2)] to intravenous single agent cisplatin (IP) (75mg/m2) given 3 weekly. Eligible patients had head and neck cancers requiring palliative chemotherapy with ECOG PS 0–2 and adequate organ functions who could not afford cetuximab. The primary end point was progression-free survival. Results110 Patients were recruited between July 2011 to May 2013, 57 randomized to the MCT arm and 53 to the IP arm. Patients in the MCT arm had significantly longer PFS (median 101days, 95% CI: 58.2–143.7days) compared to the IP arm (median 66days, 95% CI; 55.8–76.1days) (p=0.014). The overall survival (OS) was also increased significantly in the MCT arm (median 249days, 95% CI: 222.5–275.5days) compared to the IP arm (median 152days, 95% CI: 104.2–199.8days) (p=0.02). There were fewer grade 3/4 adverse effects with MCT, which was not significant. (18.9% vs. 31.4%, P=0.14). ConclusionOral metronomic chemotherapy has significantly better PFS and OS than single agent platinum in the palliative setting.

Metronomic chemotherapy in anaplastic thyroid carcinoma: A potentially feasible alternative to therapeutic nihilism

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT), and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost-effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC.

Randomized phase II trial comparing docetaxel with or without low-dose metronomic oral cyclophosphamide in first-line treatment of non-triple-negative advanced breast cancer.

1041 Background: Oral metronomic chemotherapy may target tumor cells indirectly via antiangiogenic activity, restoration of anticancer immune response, or induction of tumor dormancy. This phase II...

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.

P17. Oral metronomic chemotherapy in advanced oral squamous cell cancers: A matched pair analysis

P17. Oral metronomic chemotherapy in advanced oral squamous cell cancers: A matched pair analysis

Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy

BackgroundThe treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort.MethodsA total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls.ResultsThe median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found.ConclusionsFollow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective.

Embryonal rhabdomyosarcoma with metastases confined to the lungs: Report from the CWS Study Group

Embryonal rhabdomyosarcoma [RME] is the most common pediatric soft tissue sarcoma. Whereas the prognosis of localized rhabdomyosarcoma has improved, it remains poor for metastatic disease. We analyzed RME-patients with isolated pulmonary metastases [PRME] treated in four consecutive CWS-trials. Treatment included multiagent chemotherapy and local treatment of the primary tumor. Therapy of lung metastases after induction chemotherapy depended on response and individual decisions. Twenty-nine patients <21 years had PRME. Their median age was six years, the median follow-up nine years. Twenty-eight children had their primary tumor located in an unfavorable site and 22 of the primaries were >5 cm. In addition to conventional chemotherapy, seven patients received high-dose treatment and eight patients oral metronomic chemotherapy. The lung metastases were in remission after induction chemotherapy in 22 individuals. 19 patients received no local treatment of metastases; 3 patients had pulmonary metastasectomy and lung radiation was administered to 9 individuals. In total, 24/29 patients achieved a complete remission [CR]. Actuarial 5-year event-free and overall survival for all patients was 37.9 ± 18% and 48.7 ± 18%, respectively; it was 45.8 ± 20% and 58.3 ± 20% for the 24 patients who achieved a CR. Local treatment of metastases had no impact on the failure pattern. Younger age, good response, achievement of CR and maintenance-treatment were favorable prognostic factors in univariate analysis. Children with PRME have a fair prognosis. Local treatment of metastases did not improve outcome in our sample. Metronomic treatment may be an attractive option for PREM-patients.

Oral metronomic chemotherapy using cyclophosphamide in metastatic patients (pts) after standard treatment: Results of a randomized phase II trial

e13519 Background: Oral metronomic chemotherapy (OMC) has antiangiogenic properties and megestrol acetate (MA) is an orexigen used to maintain the general condition in critically ill pts. Anecdotal responses have been reported with each treatment. We hypothesized that each treatment offer disease control without significant severe toxicity. Methods: This multi-center-randomized study was aimed to assess the efficacy and tolerance of both treatments. Primary endpoint was stable disease rate at 2 months: 2mSD (RECIST). Main eligibility criteria were as follows: non-breast cancer, pts with progressive disease refractory to standard therapies or without established standard care, ECOG=0–1, neither hypercalcemia nor hypoalbuminemia. Pts were randomized to receive MA 160 mg b.i.d or OMC 50 mg b.i.d until severe toxicity or progression. The sample size calculation was based on Simon Minimax design (α=10%, β =90%, P0=5%, P1=20%). The second stage was allowed because at least 2mSD were seen among 12 first pts. Results: 88 pts were included from 9/2006 to 12/2008 (44 in each arm). Median age was 61 (22–84). Most common primaries were: colorectal cancer (30 pts), soft tissue sarcoma (17), lung cancer (13), head &amp; neck (8) and unknown primaries (4). The median number of previous lines of treatment was 4 (0–10). As of 28 December 2008, 80 pts are assessable for primary endpoint: 6/40 pts (15%) experienced 2mSD in OMC arm whereas 2/40 pts (5%) in MA arm. Three long-lasting SD (6 months +) are currently being observed in 3 pts receiving OMC (2 sarcomas and 1 RCC). No Grade 3 or 4 toxicity was notified. Treatment was discontinued in 1 case because of MA- induced deep venous thrombosis. Conclusions: OMC and MA offer SD in patients with advanced, refractory and progressive tumors, without any significant toxicity. The non-progression rate with OMC (15%) is in a same range of efficacy that was recently reported with new targeted therapy or anti-angiogenic agents administered in such pts. The accrual is now completed, and a longer follow-up is necessary to better analyze the clinical benefit and the prognostic factors. [Table: see text]

Durable responses with the antiangiogenic metronomic regimen RT-PEPC in elderly patients with recurrent mantle cell lymphoma (MCL)

8525 Background: Targeting tumor microenvironment and angiogenesis is a novel therapeutic strategy in lymphoma. Two putative anti-angiogenic regimens, RT (rituximab with thalidomide) and PEPC oral metronomic chemotherapy (prednisone, etoposide, procarbazine and cyclophosphamide) are clinically active. We report phase II safety, activity, and angiogenic profiling data with the novel combination RT-PEPC in elderly patients with recurrent MCL. Methods: RT-PEPC includes an induction phase (mo 1–3) of daily thalidomide (50 mg) and PEPC with weekly rituximab x 4. A maintenance phase (mo 4 until progression) continues with daily thalidomide (100 mg), PEPC dosing titrated to ANC &gt; 1K/ul, and rituximab q 4 months. Endpoints included safety, efficacy, and FACT-G quality of life (QoL) assessment. Translational studies assessed the angiogenic phenotypes of tumor cells, and dynamic levels of circulating endothelial and hematopoietic progenitors in response to treatment. Results: Twenty-five pts (19 males) were enrolled, with 22 evaluable (3 never received rx). At study entry, median age (N=25) was 68 yrs (range 52–81), 24 (96%) had stage ≥ III, 16 (64%) had LDH &gt; nl, and 18 (72%) IPI 3–5. The median number of prior therapies was two (range 1 to 7), and 15 pts (60%) progressed on bortezomib. At a median followup of 30 months, overall response rate was 73% (32% CR/CRu, 41% PR, N=22). Median PFS was 12 months, and median OS 22 months. Four CRs of 4+, 28+, 46+ and 48+ months are ongoing. Toxicities included gr 1–2 fatigue, rash and neuropathy as well as cytopenias (by design) including gr 1–2 thrombocytopenia (56%) and gr 3/4 neutropenia (56%). Two thrombotic events and 5 episodes of gr 3–4 infection were observed. QoL was maintained or improved on treatment. Correlative studies demonstrated pre-therapy autocrine angiogenic loop in tumor cells evidenced by expression of VEGFA and VEGFR1. Circulating levels of hematopoietic and endothelial progenitor cells decreased on rx in responders. Conclusions: RT-PEPC has significant and durable clinical activity in MCL, with manageable toxicity and maintained QoL. Novel low-intensity anti-angiogenic approaches warrant further evaluation in MCL and other NHL subtypes, potentially as initial therapy in elderly patients. [Table: see text]