Low-dose 5-fluorouracil Research Articles

DNA methylation drives hematopoietic stem cell aging phenotypes after proliferative stress.

Aging of hematopoietic stem cells (HSCs) is implicated in various aging phenotypes, including immune dysfunction, anemia, and malignancies. The role of HSC proliferation in driving these aging phenotypes, particularly under stress conditions, remains unclear. Therefore, we induced forced replications of HSCs in vivo by a cyclical treatment with low-dose fluorouracil (5FU) and examined the impact on HSC aging. Our findings show that proliferative stress induces several aging phenotypes, including altered leukocyte counts, decreased lymphoid progenitors, accumulation of HSCs with high expression of Slamf1, and reduced reconstitution potential, without affecting stem cell self-renewal capacity. The divisional history of HSCs was imprinted in the DNA methylome, consistent with functional decline. Specifically, DNA methylation changes included global hypermethylation in non-coding regions and similar frequencies of hypo- and hyper-methylation at promoter regions, particularly affecting genes targeted by the PRC2 complex. Importantly, initial forced replication promoted DNA damage repair accumulated with age, but continuous proliferative stress led to the accumulation of double-strand breaks, independent of functional decline. Overall, our results suggest that HSC proliferation can drive some aging phenotypes primarily through epigenetic mechanisms, including DNA methylation changes.

Low- vs High-Dose 5-FU in Triplet Chemotherapy Plus Bevacizumab for Patients With Colorectal Cancer

This cohort study examines the association of low-dose vs high-dose 5-fluorouracil with overall survival when used in triplet chemotherapy plus bevacizumab in patients from the metastatic colorectal cancer (CRC).

Acetylcorynoline Induces Apoptosis and G2/M Phase Arrest through the c-Myc Signaling Pathway in Colon Cancer Cells.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, and despite advances in treatment, survival rates are still low; therefore, the development of novel drugs is imperative. Acetylcorynoline (ACN) is derived from Corydalis ambigua Cham. et Schltdl tubers. The effect of ACN on colon cancer is still unknown. Therefore, we investigated its potential effects. Our data showed that ACN inhibited cell viability and proliferation. Moreover, ACN induced apoptosis and cell cycle arrest by inhibiting cell growth. In the present study, we hypothesized that ACN regulates c-Myc through CNOT2 or MID1IP1. ACN reduced the protein expression of oncogenic genes, decreased c-Myc half-life, and rapidly inhibited the serum stimulation response. Moreover, knockdown of CNOT2 and MID1IP1 with ACN increased apoptosis and further reduced the expression of oncogenes. In addition, ACN exhibited a synergistic effect with low-dose 5-fluorouracil (5-FU) and doxorubicin (Dox). Collectively, our data demonstrate that ACN inhibited c-Myc expression through CNOT2 and MID1IP1, and induced apoptosis. These findings indicate the potential of ACN as a therapeutic agent against colon cancer.

Intensified NK cell therapy in combination with low-dose chemoradiotherapy against human colorectal cancer.

The therapeutic potential of adoptive natural Killer (NK) cells immunotherapy in combination with chemoradiotherapy, the main treatment modality for colorectal cancer (CRC), has not yet been explored. Here, we aimed to investigate the efficacy of NK cells to potentiate primary tumor control and improve survival outcomes, especially in combination with low-dose chemoradiotherapy. Ex vivo activated NK cells (> 90% purity) from healthy donors were obtained. NK cells were administered intravenously to the CRC-bearing mice and intensified in vivo in combination with low-dose 5-fluorouracil (0.5mg/kg or 1mg/Kg) and irradiated tumors with low doses (2Gy or 4Gy). Real-time NK cell cytotoxicity demonstrated a synergistic killing effect of a combination of low-dose chemoradiotherapy, mainly through NKp30 and NKG2D, showing a decrease in NK cell degranulation after blocking NKG2D and NKp30. In vivo tumor characteristics after combination treatment showed decreased CD112, CD155, MICA, and MICB expression. Under the combination strategy, 70% of the mice had free lung metastasis and 90% without secondary gross tumors, indicating suppressed distant metastasis to lung and axillary regions. This combination therapy resulted in significantly synergistic antitumor activity against primary solid tumors compared to chemoradiotherapy only. Furthermore, the intensified NK cell administration showed significantly better primary tumor control and survival outcomes than the non-intensified NK cell administration in a human colorectal HT-29 model treated with low-dose chemoradiotherapy. Optimized NK cell therapy combined with low-dose chemoradiotherapy can provide effective therapeutic potential for intractable cold human colorectal cancer.

5-FU mediated depletion of myeloid suppressor cells enhances T-cell infiltration and anti-tumor response in immunotherapy–resistant lung tumor

Tumor microenvironment (TME) is a heterogeneous system consisting of both cellular and acellular components. The growth and progression of tumors rely greatly on the nature of TME, marking it as an important target in cancer immunotherapy. Lewis Lung Carcinoma (LLC) is an established murine lung cancer model representing immunologically ‘cold’ tumors characterized by very few infiltrated cytotoxic T-cells, high levels of Myeloid-Derived Suppressor Cells (MDSCs) and Tumor-Associated Macrophages (TAMs). Here, we report various strategies we applied to reverse the non-immunogenic character of this cold tumor by imparting: a) immunogenic cell death using Hypericin nanoparticle-based photodynamic therapy (PDT), b) repolarising TAM using a TLR7/8 agonist, resiquimod, c) immune checkpoint inhibition using anti-PD-L1 and d) depleting MDSCs using low-dose 5-fluorouracil (5-FU) chemotherapy. Interestingly, the nano-PDT, resiquimod or anti-PD-L1 treatment had no major impact on tumor growth, whereas low-dose 5-FU-mediated depletion of MDSCs showed significant anti-tumor effect, primarily caused by the increased infiltration of CD8+ cytotoxic T-cells (∼96%). Though we have tested combining PDT with resiquimod or 5-FU for any synergistic effect, low-dose 5-FU alone showed better response than combinations. In effect, we show that depletion of MDSCs using low-dose 5-FU was one of the best methods to augment infiltration of CD8+ cytotoxic T-cells into a cold tumor, which is resistant to conventional therapies including immune checkpoint inhibitors.

Treatment efficacy of low-dose 5-fluorouracil with ultrasound in mediating 5-fluorouracil-loaded microbubble cavitation in head and neck cancer

Over the past 50 years, 5-fluorouracil (5-FU) has played a critical role in the systemic chemotherapy of cancer patients. Bolus intravenous (IV) 5-FU infusion has been used due to the limitation of its extremely short half-life (10–15 min). This study used ultrasound (US) mediating 5-FU-loaded microbubbles (MBs) cavitation as a tool to increase local intratumoral 5-FU levels with a reduced dose of 5-FU (a single IV injection of 2.5 mg/kg instead of a single intraperitoneal injection of 25–200 mg/kg as used in previous studies in mice). The 5-FU-MBs were prepared with a 132 mg/mL albumin solution and a 0.30 mg/mL 5-FU solution. The diameters of the MBs and 5-FU-MBs were 1.24 ± 0.85 and 2.00 ± 0.53 µm (mean ± SEM), respectively, and the maximum loading efficiency of 5-FU on MBs was 19.04 ± 0.25%. In the in vitro study, the cell viabilities of 5-FU and 5-FU-MBs did not differ significantly, but compared with the 5-FU-MBs treatment-alone group, cell toxicity increased to 31% in the 5-FU-MBs + US group (p < 0.001). The biodistribution results indicated that the 5-FU levels of the tumors in small animals were significant higher for the 5-FU-MBs + US treatment than for either the 5-FU-MBs or 5-FU treatment with low 5-FU systemic treatment doses (2.5 mg/kg 5-FU IV). In small-animal treatment, 2.5 mg/kg 5-FU therapeutic IV doses injected into mice caused a more-significant reduction in tumor growth in the 5-FU-MBs + US group (65.9%) than in the control group after 34 days of treatment.

Synergistic Effects of the Combinational Use of Escitalopram Oxalate and 5-Fluorouracil on the Inhibition of Gastric Cancer SNU-1 Cells.

Owing to its high recurrence rate, gastric cancer (GC) is the leading cause of tumor-related deaths worldwide. Besides surgical treatment, chemotherapy is the most commonly used treatment against GC. However, the adverse events associated with chemotherapy use limit its effectiveness in GC treatment. In this study, we investigated the effects of using combinations of low-dose 5-fluorouracil (5-FU; 0.001 and 0.01 mM) with different concentrations of escitalopram oxalate (0.01, 0.02, 0.06, and 0.2 mM) to evaluate whether the assessed combination would have synergistic effects on SNU-1 cell survival. 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.06 mM) administered over 24 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Moreover, 5-FU (0.001 mM) + escitalopram oxalate (0.02 or 0.06 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.02, 0.06, or 0.2 mM) administered over 48 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Compared with controls, SNU-1 cells treated with 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) exhibited significantly increased levels of annexin V staining, reactive oxygen species, cleaved poly (ADP-ribose) polymerase, and caspase-3 proteins. Furthermore, 5-FU (12 mg/kg) + escitalopram oxalate (12.5 mg/kg) significantly attenuated xenograft SNU-1 cell proliferation in nude mice. Our study is the first to report the synergistic effects of the combinational use of low-dose 5-FU and escitalopram oxalate on inhibiting SNU-1 cell proliferation. These findings may be indicative of an alternative option for GC treatment.

Low-dose 5-fluorouracil ameliorates Th2 responses through the induction of apoptotic cell death of lung monocyte-derived dendritic cells in asthma

5-Fluorouracil (5-FU) is an analog of pyrimidine and has been shown to display antitumor and immunomodulatory effects. However, the impacts of 5-FU in regulating asthma, an inflammatory disease associated with T helper cell 2 (Th2) responses, remain unclear. Here, we determine the modulatory effects of low-dose 5-FU on Th2 cell responses in asthma and delineate the underlying mechanisms using adoptive cell transfer and in vitro culture experiments. Our data show that low-dose 5-FU treatment not only inhibits the induction of asthma in allergen-sensitized mice but also abrogates the major features of asthma in mice with established disease. We find that this protection of 5-FU treatment against asthma is accompanied by a decrease in the number of lung monocyte-derived dendritic cells (moDCs) in the asthmatic murine. Furthermore, we show that adoptive transfer of moDCs reverses the inhibitory effects of 5-FU treatment on Th2 cell responses in asthmatic mice. Surprisingly, 5-FU treatment does not suppress surface maturation markers and immunogenicity of moDCs in the lungs of asthmatic mice. Instead, it induces apoptotic cell death of mouse moDCs both in vitro and in vivo. In addition to its impact on mouse moDCs, we observe that low-dose 5-FU treatment can induce apoptotic cell death of human moDCs derived from peripheral blood mononuclear cells in vitro. Together, our findings reveal that low-dose 5-FU ameliorates Th2 cell responses, which may be at least partially related to the induction of apoptotic cell death of moDCs in asthma.

Agent-based Modeling of Tumor and Immune System Interactions in Combinational Therapy with Low-dose 5-fluorouracil and Dendritic Cell Vaccine in Melanoma B16F10.

This study is designed to present an agent-based model (ABM) to simulate the interactions between tumor cells and the immune system in the melanoma model. The Myeloid-derived Suppressor Cells (MDSCs) and dendritic cells (DCs) are considered in this model as immunosuppressive and antigen-presenting agents respectively. The animal experiment was performed on 68 B16F10 melanoma tumor-bearing C57BL/6 female mice to collect dynamic data for ABM implementation and validation. Animals were divided into 4 groups; group 1 was control (no treatment) while groups 2 and 3 were treated with DC vaccine and low-dose 5- fluorouracil (5-FU) respectively and group 4 was treated with both DC Vaccine and low-dose of 5-FU. The tumor growth rate, number of MDSC, and presence of CD8+/CD107a+ T cells in the tumor microenvironment were evaluated in each group. Firstly,the tumor cells, the effector immune cells, DCs, and the MDSCs have been considered as the agents of the ABM model and their interaction methods have been extracted from the literatureand implemented in the model. Then, the model parameters were estimated by the dynamic data collected from animal experiments. To validate the ABM model, the simulation results were compared with the real data. The results show that the dynamics of the model agents can mimic the relations among considered immune system components to an emergent outcome compatible with real data. The simplicity of the proposed model can help to understand the results of the combinational therapy and make this model a useful tool for studying different scenarios and assessing the combinational results. Determining the role of each component helps to find critical times during tumor progression and change the tumor and immune system balance in favor of the immune system.

The effect of low-dose chemotherapy on the tumor microenvironment and its antitumor activity combined with anti-PD-1 antibody.

Aim: This study aimed to explore the effects of low-dose chemotherapy in the tumor microenvironment (TME) on a gastric cancer xenograft and its antitumor activity combined with the anti-PD-1 antibody. Materials & methods: Mice with gastric cancer were divided into four groups. The body weight and tumor volume of the mice were recorded. The TME was analyzed using flow cytometry. Results: Low-dose paclitaxel increased the PD-L1 expression level and the number of CD8+ T cells, but not the CD4+ T and myeloid-derived suppressor cells or PD-1+ CD8+ T cells in the TME. Low-dose 5-fluorouracil reduced the number of myeloid-derived suppressor cells and PD-1+ CD8+ T cells, but the PD-L1 expression level and the number of CD4+ T and CD8+ T cells did not change in the TME. The anti-PD-1 antibody inhibited tumor growth, but the combination therapy did not show superior antitumor activity. Conclusion: Low-dose chemotherapy altered the TME but failed to improve the responses to the anti-PD-1 antibody.

YpN0 in Patients With Definitive cN-positive Status After Preoperative Treatment Is a Prognostic Factor in Esophageal Cancer

Histopathological tumor regression grade is applied not to lymph nodes but primary tumors modified by preoperative treatments. This study focused on patients whose pathological examination at the time of surgery showed no residual tumor after chemo(radio)therapy in the primary lesion (ypT0) or lymph nodes (ypN0). A total of 87 patients with clinical stage II/III thoracic esophageal cancer underwent esophagectomy following preoperative treatments to evaluate significances between pathological response and clinical outcomes; 51 patients with clinically definitive lymph node metastasis (cN+) were analyzed as a subgroup. ypT0 rates were 20.7% and 23.5%, and ypN0 rates were 47.1% and 27.5% in the whole cohort and in the cN+ subgroup, respectively. Disease-free survival, from surgery to relapse or death, was significantly influenced by ypN status (p=0.035) but not by ypT status in the 51 patients with definitive cN+ disease. Preoperative chemoradiation was an independent favorable factor for achievement of ypN0 in the 51 patients (odds ratio=0.09; p=0.007). ypN status was a predictive factor for DFS in patients treated with docetaxel plus low-dose 5-fluorouracil and cisplatin combined chemotherapy, superior to ypT status, especially in patients with definitive cN+ disease.

The Outcome of Chemotherapy for Metastatic Extramammary Paget’s Disease

The efficacy and survival impact of conventional chemotherapies for metastatic extramammary Paget’s disease (EMPD) have not been fully elucidated. This study examined the long-term outcome of chemotherapy for this indication. We conducted a retrospective review of 21 patients with distant metastatic EMPD (14 patients treated with chemotherapy and 7 patients treated without chemotherapy). The response rate of chemotherapy and patient survival were statistically analyzed. Among the 14 patients treated with chemotherapy, 12, 1, and 1 patient received docetaxel, paclitaxel, and low-dose 5-fluorouracil plus cisplatin, respectively, as the first-line treatment. The response rate was 50.0% (7/14), and the disease control rate was 64.3% (9/14). The median progression-free survival (PFS) and overall survival (OS) were 16.8 and 27.9 months, respectively. Multivariate analyses revealed that chemotherapy was a significant factor for prolonged PFS (hazard ratio (HR) 0.22, p = 0.038) but not for OS (HR = 1.71, p = 0.54). Ten patients (71.4%) had severe (grade 3 or 4) hematological adverse events. Although conventional chemotherapy improved PFS, we failed to show a significantly improved OS. Considering the frequent adverse events of conventional chemotherapy, targeted therapy may become a mainstay for the treatment of metastatic EMPD.

Definitive chemoradiotherapy for squamous cell carcinoma of the esophagus: outcomes for borderline-resectable disease.

Definitive chemoradiotherapy (dCRT) is the standard treatment for unresectable esophageal cancer. Induction chemotherapy has been actively investigated for borderline-resectable and unresectable disease, but the superiority over dCRT has yet to be confirmed. The purpose of this study was to evaluate the outcome of dCRT with special interest in borderline-resectable disease. Patients with esophageal cancer treated with dCRT between January 2004 and November 2016 were included in this retrospective analysis. Chemotherapy consisted of two cycles of cisplatin (70–75 mg/m2) on day 1 and 5-fluorouracil (700–1000 mg/m2 per day) on days 1–4 or low-dose cisplatin (10 mg/m2 per day) and 5-fluorouracil (175 mg/m2 per day) for 20 days. Radiotherapy was given with a daily fraction of 1.8–2 Gy to a total dose of 50–70 Gy. A total of 104 patients were included: 34 were resectable, 35 were borderline-resectable and 35 were unresectable. Complete response was achieved in 44 patients (42%). Eighteen patients (17%) suffered Grade 2 or greater cardiopulmonary toxicity and seven patients (7%) suffered Grade 3 cardiopulmonary toxicity. At the time of this analysis, 59 patients were dead and 45 were censored. The 3-year overall survival proportions for resectable, borderline-resectable and unresectable patients were 64%, 46% and 21%, respectively. The overall survival for borderline-resectable patients with complete response and noncomplete response was significantly different (P < 0.001), with 3-year survival of 70% and 8%, respectively. The overall survival for complete response patients with borderline-resectable disease was encouraging. Further investigation to find a subgroup fit for esophagus-preserving treatment is warranted.

Low Dose 5-Fluorouracil Intravaginal Therapy for the Treatment of Cervical Intraepithelial Neoplasia 2/3: A Case Series

Objective: There are no currently approved options for medical management of cervical intraepithelial neoplasia (CIN) 2/3. This article describes the use of intravaginal 5% 5-fluorouracil (5-FU) fo...

The Early Decline of α-Fetoprotein and Des-γ-Carboxy Prothrombin Predicts the Response of Hepatic Arterial Infusion Chemotherapy in Hepatocellular Carcinoma Patients

Introduction: Molecular targeting drugs are recommended as second-line treatment for intrahepatic advanced hepatocellular carcinoma (HCC). However, in Asia, hepatic arterial infusion chemotherapy (HAIC) is also considered as a second-line treatment because it improves the survival of responders. The aim of this study was to predict responders and non-responders to HAIC with low-dose cisplatin plus 5-fluorouracil (LFP) using tumor markers. Objective and Methods: The data of 47 patients who received LFP for the first time in our hospital were analyzed retrospectively. We evaluated the association between treatment response by Response Evaluation Criteria in Solid Tumors and the changing ratio of the serum concentration of α-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-γ-carboxy prothrombin (DCP) 2 weeks after LFP initiation. Results: The number of patients showing a complete response (CR), a partial response (PR), stable disease (SD), and progressive disease (PD) was 0 (0%), 20 (43%), 18 (38%), and 9 (19%), respectively. The AFP ratio showed significant positive correlations for PR vs. SD (p = 0.004) and PR vs. PD (p = 0.003). The DCP ratio correlated significantly for PR vs. SD (p = 0.02). The optimal cutoff values for responders were 0.79 for the AFP ratio and 0.53 for the DCP ratio. Prediction using both or either cutoff value showed 93% sensitivity, 53% specificity, a 94% negative predictive value, and a 57% positive predictive value. Conclusion: Optimal cutoff values for AFP and DCP ratios enable prediction of nonresponders to HAIC with LFP. This simple and early assessment method allows the use of HAIC and molecular targeting drugs for HCC treatment.

350P - Low-dose cisplatin and 5-fluorouracil combined concurrent chemoradiotherapy for unresectable cutaneous squamous cell carcinoma: Analysis of 23 cases

BackgroundCurrently, various chemotherapy regimens have been reported for the efficacy of unresectable squamous cell carcinoma (cSCC). However, there is no clear consensus. Here, we report the treatment results of unresectable cSCC in which concurrent chemoradiotherapy (CCRT) combining low-dose cisplatin and 5-fluorouracil (low-dose FP therapy) was performed in our department. MethodsA two-year retrospective study was conducted for 23 patients who had been received CCRT with low-dose FP therapy for unresectable cSCC. The patient age ranged from 44 to 79 years (mean age, 71 years), and gender was 17 men and 6 women. The primary lesions of unresectable cSCC were present in 7 cases in the head and neck, in 1 case in the upper limbs, in 5 cases in the lower limbs, and in 10 cases in the perineal region. Radiotherapy (RT) of CCRT had irradiated the primary lesion and regional lymph nodes. And for chemotherapy of CCRT, low-dose FP therapy was used. ResultsWhen 23 patients were classified by TNM staging (UICC 8th), stage 3 of unresectable cSCC was 5 patients (21.7%) and stage 4 was 18 patients (78.3%). 6 cases who those with stage 4 were dead (26.1%), while there were no dead cases who those with stage 3. Overall response rate (ORR) was 81 %, and median progression-free survival (PFS) was 392 days. For stage 4 of unresectable cSCC, one-year overall survival (OS) was 78 %, two-year OS was 56.7%, median survival time (MST) was 560 days. ConclusionsCCRT with low-dose FP therapy is an effective treatment for unresectable cSCC. However, tumors of the primary lesion and / or regional lymph nodes may remain after CCRT. In such cases, chemotherapy (i.e., maintenance therapy [MT]) should be continued after CCRT. In our department, most cases of unresectable cSCC receive MT after CCRT. Therefore, in the first treatment of unresectable cSCC, it is important how to make the tumor smaller. In this study, our cases had optimal results of ORR, median PFS, OS, and MST. According to these facts and results, we considered CCRT with low-dose FP therapy suppressed cSCC and is an effective treatment. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

A case of locally advanced cutaneous squamous cell carcinoma of the left groin treated with preoperative chemoradiation therapy containing low-dose cisplatin and 5-fluorouracil

A case of locally advanced cutaneous squamous cell carcinoma of the left groin treated with preoperative chemoradiation therapy containing low-dose cisplatin and 5-fluorouracil

An Agent-based Model for Investigating the Effect of Myeloid-Derived Suppressor Cells and its Depletion on Tumor Immune Surveillance.

Background:To predict the behavior of biological systems, mathematical models of biological systems have been shown to be useful. In particular, mathematical models of tumor-immune system interactions have demonstrated promising results in prediction of different behaviors of tumor against the immune system.Methods:This study aimed at the introduction of a new model of tumor-immune system interaction, which includes tumor and immune cells as well as myeloid-derived suppressor cells (MDSCs). MDSCs are immune suppressor cells that help the tumor cells to escape the immune system. The structure of this model is agent-based which makes possible to investigate each component as a separate agent. Moreover, in this model, the effect of low dose 5-fluorouracil (5-FU) on MDSCs depletion was considered.Results:Based on the findings of this study, MDSCs had suppressive effect on increment of immune cell number which consequently result in tumor cells escape the immune cells. It has also been demonstrated that low-dose 5-FU could help immune system eliminate the tumor cells through MDSCs depletion.Conclusion:Using this new agent-based model, multiple injection of low-dose 5-FU could eliminate MDSCs and therefore might have the potential to be considered in treatment of cancers.

Low-Dose Continuous 5-Fluorouracil Combined with Leucovorin, nab-Paclitaxel, Oxaliplatin, and Bevacizumab for Patients with Advanced Pancreatic Cancer: A Retrospective Analysis.

BackgroundContinuous-infusion 5-fluorouracil (5FU) and calcium leucovorin plus nab-paclitaxel and oxaliplatin have been shown to be active in patients with pancreatic cancer. As a protracted low-dose infusion, 5FU is antiangiogenic, and has synergy with bevacizumab. As shown in the treatment of breast cancer, bevacizumab and nab-paclitaxel are also synergetic.ObjectiveIn this paper we retrospectively analyze the survival of 65 patients with advanced pancreatic cancer who were treated with low-dose continuous (metronomic) chemotherapy given in conjunction with conventional anti-VEGF therapy.Patients and MethodsSince July of 2008, we have treated 65 patients with 5FU (180 mg/m2/day × 14 days) via an ambulatory pump. Calcium leucovorin (20 mg/m2 IV), nab-paclitaxel (60 mg/m2) IV as a 30-min infusion, and oxaliplatin (50 mg/m2) IV as a 60-min infusion were given on days 1, 8, and 15. Bevacizumab (5 mg/kg) IV over 30 min was administered on days 1 and 15. Cycles were repeated every 28–35 days. There were 42 women and 23 men, and the median age was 59 years. Forty-six patients had stage IV disease.ResultsThe median survival was 19 months, with 82% of patients surviving 12 months or longer. The overall response rate was 49%. There were 28 patients who had received prior treatment, 15 of whom responded to therapy. Fifty-two patients had elevated CA 19-9 prior to treatment. Of these, 21 patients had 90% or greater reduction in CA 19-9 levels. This cohort had an objective response rate of 71% and a median survival of 27 months. Thirty patients stopped treatment due to disease progression, and an additional 22 stopped because of toxicity. One patient died while on therapy.ConclusionsThis non-gemcitabine-based regimen resulted in higher response rates and better survival than what is commonly observed with therapy given at conventional dosing schedules. Low-dose continuous (metronomic therapy) cytotoxic chemotherapy combined with antiangiogenic therapy is safe and effective.

Definitive chemoradiotherapy with low-dose continuous 5-fluorouracil reduces hematological toxicity without compromising survival in esophageal squamous cell carcinoma patients

Background and purposeTo compare chemoradiotherapy (CRT) with low-dose continuous 5-fluorouracil (5FU) to CRT with 5FU+cisplatin (CDDP) for esophageal squamous cell carcinoma (ESCC) in a retrospective cohort study. Methods and materialsWe reviewed the cases of Stage I–IV ESCC patients who underwent definitive CRT in 2000–2014. Concomitant chemotherapy was one of the three regimens: (1) high-dose intermittent 5FU and CDDP (standard-dose FP: SDFP), (2) low-dose continuous 5FU and CDDP (LDFP), or (3) low-dose continuous 5FU (LD5FU). The general selection criteria for chemotherapy were: SDFP for patients aged <70 yrs; LDFP for those aged 70–74 yrs; LD5FU for those aged ≥75 yrs or with performance status (PS) ≥3. Propensity scores were derived with chemotherapy (LD5FU vs. 5FU+CDDP) as the dependent variable. ResultsIn a multivariate analysis, chemotherapy (LD5FU vs. SDFP, p = .24; LDFP vs. SDFP, p = .52) did not affect the overall survival (OS). LD5FU caused significantly less grade 3–4 leukopenia (9%) compared to SDFP (47%) and LDFP (44%) (p < .001). In a propensity-matched analysis, LD5FU affected neither OS (HR 1.06; 95%CI 0.55–2.05; p = .87) nor progression-free survival (HR 0.95, 95%CI 0.50–1.81; p = .87). ConclusionCRT with low-dose continuous 5FU may be a less toxic option for elderly ESCC patients.