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Cancer Research Communications Nov 2022The treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) is frequently characterized by significant toxicity and rapid development of resistance to current...
UNLABELLED
The treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) is frequently characterized by significant toxicity and rapid development of resistance to current approved therapies. More reliable biomarkers of response are needed to guide clinical decision making. We evaluated cell-free DNA (cfDNA) using a tumor-agnostic platform and traditional biomarkers (CEA and CA19-9) levels in 12 patients treated at Johns Hopkins University on NCT02324543 "Study of Gemcitabine/Nab-Paclitaxel/Xeloda (GAX) in Combination With Cisplatin and Irinotecan in Subjects With Metastatic Pancreatic Cancer." The pretreatment values, levels after 2 months of treatment, and change in biomarker levels with treatment were compared with clinical outcomes to determine their predictive value. The variant allele frequency (VAF) of and mutations in cfDNA after 2 months of treatment was predictive of progression-free survival (PFS) and overall survival (OS). In particular, patients with a lower-than-average VAF after 2 months of treatment had a substantially longer PFS than patients with higher posttreatment VAF (20.96 vs. 4.39 months). Changes in CEA and CA19-9 after 2 months of treatment were also good predictors of PFS. Comparison via concordance index demonstrated or VAF after 2 months of treatment to be better predictors of PFS and OS than CA19-9 or CEA. This pilot study requires validation but suggests cfDNA measurement is a useful adjunct to traditional protein biomarkers and imaging evaluation and could distinguish between patients who are likely to achieve prolonged responses versus those that will have early progression and may benefit from a change in treatment approach.
SIGNIFICANCE
We report on the association of cfDNA with response durability for patients undergoing treatment with a novel metronomic chemotherapy regimen (gemcitabine, nab-paclitaxel, capecitabine, cisplatin, irinotecan; GAX-CI) for metastatic PDAC. This investigation offers encouraging evidence that cfDNA may prove to be a valuable diagnostic tool to guide clinical management.
Topics: Humans; Irinotecan; Cisplatin; Deoxycytidine; Cell-Free Nucleic Acids; CA-19-9 Antigen; Pilot Projects; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Capecitabine
PubMed: 36970054
DOI: 10.1158/2767-9764.CRC-22-0343 -
In Vivo (Athens, Greece) 2018The aim of the present study was to evaluate a multimodal approach for the treatment of canine malignant mammary gland neoplasms, including surgery, chemotherapy,...
BACKGROUND/AIM
The aim of the present study was to evaluate a multimodal approach for the treatment of canine malignant mammary gland neoplasms, including surgery, chemotherapy, thalidomide, and metronomic chemotherapy (MC).
MATERIALS AND METHODS
Fifty-eight female dogs were submitted to four different treatments: surgery; surgery with chemotherapy; surgery with chemotherapy and thalidomide; and surgery with chemotherapy and metronomic chemotherapy and overall survival was evaluated.
RESULTS
No statistical difference was found in the proliferative index and microvessel density of primary neoplasms and distant metastases following thalidomide treatment. Diffuse intense inflammatory infiltrate was predominant in primary tumors and diffuse moderate inflammatory infiltrate in metastatic lesions. No statistically significant difference was observed in median survival time (MST) between treatment groups when including all clinical stages (p=0.3177). However, animals diagnosed with distant metastasis treated with surgery and chemotherapy associated with thalidomide or MC presented longer MST when compared to animals treated only with surgery or surgery and chemotherapy (p<0.0001).
CONCLUSION
The proposed multimodal therapy protocols including antiangiogenic and immunomodulatory therapies demonstrated a clinical benefit for patients in advanced clinical stages.
Topics: Administration, Metronomic; Angiogenesis Inhibitors; Animals; Chemotherapy, Adjuvant; Combined Modality Therapy; Dog Diseases; Dogs; Female; Humans; Mammary Neoplasms, Animal; Thalidomide
PubMed: 30348731
DOI: 10.21873/invivo.11429 -
EMBO Molecular Medicine Sep 2020Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically...
Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia-inducible factor (HIF)-1α and (HIF)-2α (hereafter referred to as HIFα). Instead, frequent low-dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre-clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog-specific, MTD-dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11-gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα-targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra-metastatic tumor microenvironment.
Topics: Breast Neoplasms; Female; Humans; Lung Neoplasms; Maximum Tolerated Dose; Neoplasm Recurrence, Local; Tumor Microenvironment
PubMed: 32686360
DOI: 10.15252/emmm.201911416 -
Translational Oncology Nov 2021Although sorafenib, a molecular targeted agent, has survival benefits for advanced hepatocellular carcinoma (HCC) patients, its disease control rate remains limited. To...
OBJECTIVE
Although sorafenib, a molecular targeted agent, has survival benefits for advanced hepatocellular carcinoma (HCC) patients, its disease control rate remains limited. To explore the potential for augmenting its antitumor effect, we assessed the preclinical and clinical efficacy and tolerability of S-1 metronomic chemotherapy (MC) plus sorafenib.
METHODS
Antitumor effects and toxicity of this combination were tested with HAK-1B xenograft and spontaneous HCC mouse models, and a prospective pilot study was performed to compare therapeutic effects and safety between sorafenib plus MC S-1 for 12 advanced HCC cases and the historical control of 363 sorafenib-treated advanced HCC patients at our hospital from July 2011 to June 2015.
RESULTS
In mice, the combination chemotherapy enhanced anti-angiogenic effects, resulting in a stronger tumor hypoxic environment and increased tumor cell apoptosis. Clinically, the objective response rate of the combination chemotherapy was higher than that of sorafenib mono therapy (16.7%; 2/12 vs 5.2%; 19/363, p < 0.05); however, there were no significant differences in overall survival and time to progression. Adverse events including alopecia, thrombocytopenia, and pancreatic enzymes elevation in the combination chemotherapy were higher than those of sorafenib. No patient treated with the combination chemotherapy discontinued treatment due to severe adverse events.
CONCLUSIONS
Sorafenib plus MC S-1 seems to be effective and tolerable for patients with advanced HCC and could be considered a treatment option for these patients.
PubMed: 34388691
DOI: 10.1016/j.tranon.2021.101201 -
Taiwanese Journal of Obstetrics &... Jun 2012Systemic administration of cytotoxic drugs is the primary treatment strategy for patients with advanced cancer. The effect of cytotoxic drugs is to disrupt the DNA of... (Review)
Review
Systemic administration of cytotoxic drugs is the primary treatment strategy for patients with advanced cancer. The effect of cytotoxic drugs is to disrupt the DNA of the cells, rendering them unable to replicate and finally killing them; therefore, the fundamental role of a wide range of treatment regimens is typically to induce lethal toxicity in the largest possible number of cancer cells. However, these cytotoxic drugs also damage the normal cells of the host, which limits the dose of the cytotoxic drug. Thus, cancer patients are usually treated at or near the maximum tolerated dose with the implicit intent of eradicating (curing) the tumor after balancing between efficacy in tumor killing and toxicity to the host. With significantly improving patient care, most efforts are focused on the corollary, "The higher the dose, the better." However, the concept that cancer could be considered as a chronic disease and might be treated like other chronic diseases to achieve a status called tumor dormancy is gaining popularity. In addition, there has been increasing interest in putting more effort into administering cytotoxic drugs on a more continuous basis, with a much shorter break period, or none at all, and generally lower doses of various cytotoxic drugs or combinations with other newer, targeted therapies, like anti-angiogenesis agents. This practice has come to be known as metronomic chemotherapy. There is still much to be learned in this field, especially with regard to optimization of the proper drugs, dose, schedule, and tumor type applications. This review will explore recent studies that have addressed the mechanism of metronomic chemotherapy in the management of various tumors, especially gynecologic cancers.
Topics: Administration, Metronomic; Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Female; Humans; Molecular Targeted Therapy; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Uterine Cervical Neoplasms; Uterine Neoplasms
PubMed: 22795090
DOI: 10.1016/j.tjog.2012.04.002 -
Journal of B.U.ON. : Official Journal... 2021The purpose of this study was to investigate the efficacy and safety of maintenance therapy of capecitabine metronomic chemotherapy combined with autologous...
PURPOSE
The purpose of this study was to investigate the efficacy and safety of maintenance therapy of capecitabine metronomic chemotherapy combined with autologous cytokine-induced killer (CIK) cell immunotherapy in patients with recurrent metastatic triple-negative breast cancer (mTNBC).
METHODS
The clinical data of 110 patients with recurrent mTNBC were retrospectively analyzed. Among, 55 were treated with maintenance therapy of capecitabine metronomic chemotherapy combined with autologous CIK cell immunotherapy (DC-CIK group), while the rest 55 were treated with simple metronomic chemotherapy (control group).
RESULTS
The ORR of patients in DC-CIK group and control group was 29.1% and 16.4%, and the DCR was 74.5% and 63.6%, respectively. After treatment, the proportions of CD3+ T lymphocytes, CD4+ T lymphocytes and NK cells as well as the CD4/CD8 cell ratio were notably higher in DC-CIK group than those in control group, while the proportion of CD8+ T lymphocytes was notably lower in DC-CIK group than that in control group. Compared with those before treatment, the scores of quality of life evaluated using the FACT-B-V4.0 scale were remarkably improved in both groups after treatment. The score of emotional status and total score were distinctly higher in DC-CIK group than those in control group. Moreover, the follow-up results together with log-rank test revealed that the PFS in DC-CIK group was notably superior to that in control group.
CONCLUSIONS
The maintenance therapy of capecitabine metronomic chemotherapy combined with DC-CIK cell immunotherapy is effective in the treatment of recurrent mTNBC, with tolerable adverse reactions. It can improve the patients' immune function, improve their quality of life, and prolong their PFS. Key words: capecitabine, metronomic chemotherapy, immunotherapy, breast cancer, recurrent and metastatic.
Topics: Administration, Metronomic; Adult; Antimetabolites, Antineoplastic; Capecitabine; Combined Modality Therapy; Cytokine-Induced Killer Cells; Female; Humans; Immunotherapy, Adoptive; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies; Treatment Outcome; Triple Negative Breast Neoplasms
PubMed: 34268928
DOI: No ID Found -
Oncology (Williston Park, N.Y.) Apr 2005The improved survival associated with adding the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to chemotherapy for the... (Review)
Review
The improved survival associated with adding the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to chemotherapy for the treatment of patients with metastatic colorectal cancer demonstrates the importance of targeting collateral cells involved in tumor growth, progression, and metastatic spread. Based on the Gompertzian model of tumor growth, adding anti-VEGF agents to standard chemotherapy may be especially effective in early stages of cancer. By improving chemotherapy delivery to the tumor and inhibiting regrowth between treatment cycles, anti-VEGF agents may alter the growth pattern of a tumor such that it is more susceptible to eradication. These concepts also suggest that anti-VEGF agents could enhance the effectiveness of chemotherapy given conventionally or in a dose-dense fashion. As such, it is possible that the effectiveness of chemotherapy could be maintained or improved, even at lower cumulative doses, which may improve its tolerability. Additionally, the effects of anti-VEGF agents on metronomic chemotherapy, which is reported to have antiangiogenic properties on its own, warrant further evaluation. Preclinical data demonstrate that cytostatic angiogenesis inhibitors are potent complementary agents to metronomic chemotherapy, producing sustained complete regressions in some models of human cancer. Dose-dense and metronomic chemotherapy have in common a shortened dosing interval and resultant increased and/or prolonged exposure of tumor cells to chemotherapy in vivo. Optimizing the use of anti-VEGF agents in the clinic demands further investigation of the most appropriate way to combine them with chemotherapy, particularly regimens designed to exploit known tumor growth patterns and those designed to target the endothelial cells involved in neovascularization with multiple agents.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Drug Delivery Systems; Humans; Medical Oncology; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A
PubMed: 15934500
DOI: No ID Found -
Neoplasia (New York, N.Y.) Mar 2011Metronomic chemotherapy involves frequent, regular administration of cytotoxic drugs at nontoxic doses, usually without prolonged breaks. We investigated the therapeutic...
BACKGROUND
Metronomic chemotherapy involves frequent, regular administration of cytotoxic drugs at nontoxic doses, usually without prolonged breaks. We investigated the therapeutic efficacies of metronomic S-1, an oral 5-fluorouracil prodrug, and vandetanib, an epidermal growth factor receptor and vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, in models of hepatocellular carcinoma (HCC).
METHODS
We compared anti-HCC effects and toxicity in the six treatment groups: control (untreated), maximum tolerated dose (MTD) S-1, metronomic S-1, vandetanib, MTD S-1 with vandetanib, and metronomic S-1 with vandetanib. Tumor microvessel density (MVD) and tumor apoptosis were evaluated by immunohistochemistry. The expression of VEGF and thrombospondin-1, an endogenous inhibitor of angiogenesis, was analyzed by Western blot.
RESULTS
Metronomic S-1 significantly inhibited tumor growth, which was enhanced by combination with vandetanib. With respect to toxicities, MTD S-1 caused severe body weight loss and myelosuppression, whereas metronomic S-1 did not cause any overt toxicities. Moreover, metronomic S-1 or metronomic S-1 with vandetanib prolonged survival, the latter treatment providing the greatest benefit. Metronomic S-1 and metronomic S-1 with vandetanib decreased MVDs and increased apoptosis in tumor tissues. The expression of VEGF in tumor tissues was upregulated by vandetanib and metronomic S-1 with vandetanib, whereas the expression of thrombospondin-1 was upregulated by metronomic S-1 and metronomic S-1 with vandetanib.
CONCLUSION
Metronomic S-1 with an antiangiogenic agent seems to be an effective and safe therapeutic strategy for HCC.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Drug Combinations; ErbB Receptors; Fluorouracil; Humans; Immunoenzyme Techniques; Lung Neoplasms; Male; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Mice, Nude; Oxonic Acid; Piperidines; Quinazolines; Tegafur; Tumor Cells, Cultured
PubMed: 21390182
DOI: 10.1593/neo.101186 -
Cancer Letters Jun 2024Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting... (Review)
Review
Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting multiple targets and reducing toxicity of antineoplastic drugs. This minireview will summarize preclinical and clinical studies on cytotoxic drugs given at weekly, daily, or at continuous metronomic schedules alone or in combination with novel targeted agents for hematological malignancies, including lymphoma, multiple myeloma, and leukemia. Most of the preclinical in vitro and in vivo studies have reported a significant benefit of both mCHEMO monotherapy and combinatorial regimens compared with chemotherapy at the maximum tolerated dose. However, the combination of mCHEMO with targeted drugs is still little explored in the hematologic clinical setting. Data obtained from preclinical studies on low dose metronomic chemotherapy in hematological malignancies clearly suggested the possibility to clinically investigate more tolerable and effective strategies for the treatment of patients with advanced hematological malignancies, or at least for those frail and elderly patients, who are not eligible or resistant to standard treatments.
Topics: Humans; Administration, Metronomic; Hematologic Neoplasms; Antineoplastic Agents; Animals; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38636896
DOI: 10.1016/j.canlet.2024.216900 -
Hormones & Cancer Dec 2011Metronomic chemotherapy is the administration of cytotoxic drugs at low doses, on a frequent or continuous schedule, with no extended interruption. This treatment... (Review)
Review
Metronomic chemotherapy is the administration of cytotoxic drugs at low doses, on a frequent or continuous schedule, with no extended interruption. This treatment approach can target tumor cells indirectly since it can affect the endothelium of the growing tumor vasculature and stimulates the anticancer immune response. Both the antiangiogenetic and the immunomodulatory roles of metronomic chemotherapy favor a tumor dormancy, a condition that may improve the patient outcome. Prospective clinical trials conducted in several malignancies have shown that metronomic chemotherapy can obtain disease stabilization or responses in tumors that had been made resistant in vivo to conventional chemotherapeutic regimens. Three prospective phase II trials have been conducted in patients with adrenocortical carcinoma (ACC). In all of them, patients heavily pretreated with conventional chemotherapy and mitotane have been enrolled. One trial tested the activity of the association of gemcitabine and fluoropyrimidines administered on a metronomic schedule. In this trial, 40% of patients attained a disease stabilization or disease response that was long lasting in some of them. In the remaining two trials, metronomic chemotherapy was administered in association with antiangiogenetic drugs, and the results were disappointing since no response or stable disease was obtained. In conclusion, metronomic chemotherapy can delay tumor progression in advanced ACC and deserves to be further tested. The concomitant administration of antiangiogenetic drugs may be detrimental. Several important questions remain to be addressed such as the optimal dose and most effective dosing interval, when to use the metronomic approach in the natural history of the disease, the choice of cytotoxic drugs, and the most efficacious way to integrate metronomic chemotherapy with standard therapy protocols.
Topics: Administration, Metronomic; Adrenal Gland Neoplasms; Adrenocortical Carcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Endothelium, Vascular; Humans; Immunity; Mitotane; Neovascularization, Pathologic; Treatment Outcome
PubMed: 21971765
DOI: 10.1007/s12672-011-0087-1