Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer.

PURPOSE: Convincing data support the link between inflammation and ovarian cancer. Tumor necrosis factor-alpha (TNF-alpha), a major mediator of inflammation, is chronically produced in the ovarian tumor microenvironment and may enhance tumor growth and invasion by inducing the secretion of cytokines, proangiogenic factors, and metalloproteinases. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-alpha and renders it biologically unavailable. In the current study, we sought to determine the toxicity, biologic activity, and therapeutic efficacy of etanercept in recurrent ovarian cancer. PATIENTS AND METHODS: We initiated a phase I-B, nonrandomized, open-label study in patients with recurrent ovarian cancer. Etanercept was administered subcutaneously at a dose of 25 mg twice weekly (cohort one) and 25 mg thrice weekly (cohort two) until disease progression. RESULTS: Thirty patients were recruited (cohort one, 17 patients; cohort two, 13 patients). Eighteen of the 30 patients (cohort one, 11 patients; cohort two, seven patients) completed > or = 12 weeks of treatment. Six patients achieved prolonged disease stabilization (cohort one, two patients [40 and 25 weeks]; cohort two, four patients [34, 24, 22, and 24 weeks]). A significant rise in immunoreactive TNF was seen in all patients (pretreatment compared with end of treatment). A phytohemagglutinin-stimulated whole-blood cytokine assay showed a significant fall in interleukin-6 (cohort one [11 of 17]) and CCL2 (cohort one [13 of 17]) levels. Common adverse effects were injection-site reactions and fatigue. CONCLUSION: We provide evidence for the biologic activity and safety of etanercept in recurrent ovarian cancer. Our data suggest possible clinical activity that must be confirmed in future studies.     

Impaired production of tumor necrosis factor in breast cancer

Spontaneous and lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF) by peripheral blood macrophages was investigated in breast cancer. Whereas spontaneous TNF production by macrophages derived from patients with breast cancer was comparable with the one found in healthy controls (P greater than 0.1), LPS-stimulated macrophages derived from patients in the disease-free interval as well as with metastatic breast cancer were found to produce significantly lower amounts of TNF, as compared with macrophages derived from healthy control individuals (P less than 0.0005). However, the production of TNF did not significantly differ between the two patient populations (P greater than 0.05). The impairment of LPS-induced TNF production did not depend upon such characteristics of the primary tumor as size, axillary lymph node and estrogen receptor status, or upon the fact of administration of adjuvant chemotherapy and, in patients with metastatic disease, hormone treatment. To further investigate cytokine production by macrophages, spontaneous and LPS-induced interleukin-1 (IL-1) production was investigated also. However, no difference was found between patients and controls concerning IL-1 generation. The authors thus conclude that LPS-induced TNF production was impaired in breast cancer independent of the presence of detectable metastatic disease, whereas IL-1 production remained unimpaired.     

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.     

A Southwest Oncology Group phase II Trial of recombinant tumor necrosis factor in metastatic breast cancer

New approaches are needed in the treatment of advanced breast cancer. In vitro studies have shown that recombinant tumor necrosis factor (TNF) is a growth inhibitor for the MCF-7, ZR-75-1, and BT-20 human breast cancer cell lines. Based on these considerations, the Southwest Oncology Group performed a Phase II trial of recombinant TNF (Genentech) (150 micrograms/m2) given by 30-minute intravenous infusion on days 1 to 5 of every other week for 8 weeks. Patients with metastatic breast cancer who had received one prior chemotherapy regimen for advanced disease were eligible. Of the 22 patients who were entered, 3 were ineligible. Nineteen patients who had a performance status of 2 or less could be examined (median age, 53 years). One possible fatal toxic reaction has been seen in a patient who had intracranial bleeding caused by a previously undiagnosed brain metastasis; no other treatment-related deaths have occurred. Toxicity has included nausea, vomiting, fever, chills, myalgia, and fatigue. No Grade 4 toxicity has been observed. Grade 3 toxic reactions have included hypotension (two patients), diarrhea (one patient), transient leukopenia (two patients), and reversible elevations of liver function test values (two patients). No objective responses have been observed. Twelve of 19 patients have died (median survival time, 8.5 months). Recombinant TNF is inactive as a single agent in patients with previously treated metastatic breast cancer.     

Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer

Background

The inflammatory chemokines CCL2 (MCP-1) & CCL5 (RANTES) and the inflammatory cytokines TNFα & IL-1β were shown to contribute to breast cancer development and metastasis. In this study, we wished to determine whether there are associations between these factors along stages of breast cancer progression, and to identify the possible implications of these factors to disease course.

Methods

The expression of CCL2, CCL5, TNFα and IL-1β was determined by immunohistochemistry in patients diagnosed with: (1) Benign breast disorders (=healthy individuals); (2) Ductal Carcinoma In Situ (DCIS); (3) Invasive Ducal Carcinoma without relapse (IDC-no-relapse); (4) IDC-with-relapse. Based on the results obtained, breast tumor cells were stimulated by the inflammatory cytokines, and epithelial-to-mesenchymal transition (EMT) was determined by flow cytometry, confocal analyses and adhesion, migration and invasion experiments.

Results

CCL2, CCL5, TNFα and IL-1β were expressed at very low incidence in normal breast epithelial cells, but their incidence was significantly elevated in tumor cells of the three groups of cancer patients. Significant associations were found between CCL2 & CCL5 and TNFα & IL-1β in the tumor cells in DCIS and IDC-no-relapse patients. In the IDC-with-relapse group, the expression of CCL2 & CCL5 was accompanied by further elevated incidence of TNFα & IL-1β expression. These results suggest progression-related roles for TNFα and IL-1β in breast cancer, as indeed indicated by the following: (1) Tumors of the IDC-with-relapse group had significantly higher persistence of TNFα and IL-1β compared to tumors of DCIS or IDC-no-relapse; (2) Continuous stimulation of the tumor cells by TNFα (and to some extent IL-1β) has led to EMT in the tumor cells; (3) Combined analyses with relevant clinical parameters suggested that IL-1β acts jointly with other pro-malignancy factors to promote disease relapse.

Conclusions

Our findings suggest that the coordinated expression of CCL2 & CCL5 and TNFα & IL-1β may be important for disease course, and that TNFα & IL-1β may promote disease relapse. Further in vitro and in vivo studies are needed for determination of the joint powers of the four factors in breast cancer, as well as analyses of their combined targeting in breast cancer.     

Phase I trial of TALL-104 cells in patients with refractory metastatic breast cancer.

The human cytotoxic T-cell line TALL-104 displays antitumor effects in animals with implanted and spontaneous malignancies. A Phase I trial was conducted to determine toxicity of TALL-104 cell therapy in women with metastatic refractory breast cancer. Fifteen patients with metastatic infiltrating ductal (n = 12), lobular (n = 2), or medullary (n = 1) carcinoma received escalating doses of lethally irradiated TALL-104 cells (three patients/group received 10(6), 3 x 10(6), 10(7), 3 x 10(7), and 10(8) cells/kg) for 5 consecutive days (induction course). Patients without progressive disease received monthly maintenance 2-day infusions at the same dose level. Mild grade I/II toxicity developed in 11 patients regardless of cell dose. One grade IV toxicity consequent to hepatic tumor necrosis occurred in a patient given 10(8) cells/kg, 3 weeks after the induction course. Nine patients progressed within 1 month from induction, and five patients had stable disease for 2-6 months. One patient (at 3 x 10(7)/kg) had improvement of liver metastases and ascites, and a second patient (at 10(6)/kg) experienced a dramatic relief in bone pain. Increases in blood natural killer cell activity and levels of IFN-gamma, interleukin-10, and activation markers (soluble interleukin-2 receptor and soluble intercellular adhesion molecule-1) were often seen. Only one patient developed anti-HLA class I antibody responses against TALL-104 cells; specific CTL activity developed in three patients during induction and in four patients during the maintenance boosts. In conclusion, TALL-104 cells were well tolerated by patients with metastatic breast cancer at the doses and regimen tested. The clinical responses observed in this preliminary trial demonstrate that further investigation of TALL-104 cell therapy is warranted.     

A Phase 2 study of perifosine in advanced or metastatic breast cancer

Background First- and second-line chemotherapy with anthracyclines and taxanes in metastatic breast cancer yield a modest improvement in survival with potentially significant toxicity. Subsequent lines of chemotherapy yield response rates of 20–25%, with an unknown impact on survival. Perifosine, an oral alkylphospholipid structurally related to miltefosine, has marked activity against breast cancer cell lines and xenograft models, with broad spectrum cellular effects. Objectives To determine the efficacy and toxicity of perifosine in patients with metastatic breast cancer patients after up to 2 lines of prior chemotherapy for advanced disease. Methods 18 patients were enrolled, and 17 treated, using a loading/maintenance dose schedule, (day 1, 300 mg, maintenance 150 mg days 2–21) every 28 days, until disease progression or unacceptable toxicity. Results Median age of patients was 54 (28–69), 16/17 were female, ECOG performance status was 0/1 in 16 patients. Fifteen received at least 1 prior chemotherapy regimen for metastatic disease (maximum 2). A median of 2 cycles (range 1–13) was administered per patient. Sixteen were evaluable for response: 2 had SD for 4 cycles, 1 SD for 13 cycles, 13 progressed by cycle 2. Grade 3/4 drug-related non-hematologic toxicities include: diarrhea (2), vomiting (2), nausea (2), fatigue (2) and anorexia (1). No grade 3/4 hematologic toxicities were seen. Median time to progression was 8 weeks (7–15 weeks). Conclusion No objective responses were seen in this group of pretreated metastatic breast cancer patients. Disease stabilization was observed in 19% at 2 months. Supported through NIH/NCI Phase 2 Consortium N01-CM-17107 Grant. N. B. Leighl is the principal investigator. Princess Margaret Hospital Phase 2 Consortium, Ontario, Canada includes Princess Margaret Hospital/University Health Network, Toronto; The Ottawa Hospital Regional Cancer Centre, Ottawa; London Regional Cancer Centre, London; Juravinski Cancer Centre, Hamilton.     

Integrative Bioinformatics Analysis Reveals Potential Target Genes and TNFα Signaling Inhibition by Brazilin in Metastatic Breast Cancer Cells

Objective: Metastasis is the most significant cause of morbidity and mortality in breast cancer patients. Previously, a combination of brazilin and doxorubicin has been shown to inhibit metastasis in HER2-positive breast cancer cells. This present study used an integrative bioinformatics approach to identify new targets and the molecular mechanism of brazilin in inhibiting metastasis in breast cancer. Methods: Cytotoxicity and mRNA arrays data were retreived from the DTP website, whereas genes that regulate metastatic breast cancer cells were retreived from PubMed with keywords “breast cancer metastasis”. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Drug association analysis were carried out by using WEB-based GEne SeT AnaLysis Toolkit (WebGestalt). Construction of protein-protein interaction (PPI) network analysis was performed by STRING-DB v11.0 and Cytoscape, respectively. The genetic alterations of the potential therapeutic target genes of brazilin (PB) were analyzed using cBioPortal. Results: Analysis of cytotoxicity with the public database of COMPARE showed that brazilin exerts almost the same cytotoxicity in the NCI-60 cells panel showing by similar GI50 value, in which the lowest GI50 value was observed in MDA-MB 231, a metastatic breast cancer cells. KEGG enrichment indicated several pathways regulated by brazilin such as TNF signaling pathway, cellular senescence, and pathways in cancer. We found ten drugs that are associated with PB, including protein kinase inhibitors, TNFα inhibitors, enzyme inhibitors, and anti-inflammatory agents. Conclusion: In conclusion, this study identified eight PB, including MMP14, PTGS2, ADAM17, PTEN, CCL2, PIK3CB, MAP3K8, and CXCL3. In addition, brazilin possibly inhibits metastatic breast cancer through inhibition of TNFα signaling. The study results study need to be validated with in vitro and in vivo studies to strengthen scientific evidence of the use of brazilin in breast cancer metastasis inhibition.     

A pilot phase II trial of valspodar modulation of multidrug resistance to paclitaxel in the treatment of metastatic carcinoma of the breast (E1195): a trial of the Eastern Cooperative Oncology Group

Background: To assess the activity and toxicity of valspodar (PSC-833) in combination with paclitaxel in women with anthracycline refractory, metastatic breast cancer. Patients and Methods: Limited, multi-institutional, Phase II trial of valspodar at 5 mg/kg/dose orally every 6 hours for 12 doses in combination with paclitaxel 70 mg/m² administered intravenously as a 3-hour infusion beginning 4 hours after the fifth dose of valspodar, every 3 weeks. Eligible patients had bi-dimensionally measurable metastatic carcinoma of the breast, prior anthracycline therapy or a medical contraindication to anthracycline therapy, no more than one prior chemotherapy for recurrent or metastatic breast cancer, and adequate organ function. Treatment was continued until disease progression or unacceptable toxicity. Results: Thirty-four patients are evaluable for response and 37 for toxicity. Two (6 percent) patients achieved a complete response and 5 (15 percent) a partial response for an objective response rate of 21 percent (95 percent confidence interval of 9 to 38 percent). Median duration of response was 9.7 months (95 percent confidence interval 8.0-17.2 months), median time to progression was 3.3 months (95 percent confidence interval 2.0-4.2 months), and median survival was 12 months (95 percent confidence interval 8.1-17.3 months). The toxicity experienced was acceptable. Conclusions: Combination valspodar plus paclitaxel is an active regimen and has acceptable toxicity. The combination is not clearly more active than single agent paclitaxel.     

中等剂量卡培他滨单药治疗转移性乳腺癌的疗效及安全性

目的观察中等剂量［2 000 mg/(m²·d)］卡培他滨治疗转移性乳腺癌的疗效和不良反应。方法卡培他滨单药治疗43例转移性乳腺癌,2000 mg/(m²·d),d1～14,每3周为1周期。结果43例患者平均行8周期卡培他滨治疗,客观缓解率（CR+PR）为18.6%,临床获益率（CR+PR+SD）为86.0%。整体的中位无进展生存期（PFS）为7.1月（95%CI：5.8～8.4）,在一线治疗、二线治疗和三线及以上治疗亚组中差异无统计学意义,分别为7.1月、6.1月和8.1月（P=0.390）。在蒽环类药物与紫杉类药物治疗均失败的患者中,PFS明显缩短（6.1月 vs.7.1月,P=0.038）。大于65岁的患者PFS显著延长（8.1月 vs.6.1月,P=0.045）。主要不良反应为手足综合征19例（44.2%）。结论中等剂量［2 000 mg/(m²·d)］卡培他滨单药治疗转移性乳腺癌安全、有效。     

Trastuzumab and interleukin-2 in HER2-positive metastatic breast cancer: a pilot study.

PURPOSE: Trastuzumab as a single agent has activity in metastatic breast cancer; however, the mechanism of action for this clinical activity is uncertain. Whereas interruption of erbB family member signaling occurs, trastuzumab also mediates antibody-dependent cellular cytotoxicity in vitro and in vivo. Based on these data, a clinical trial was performed to test whether interleukin (IL)-2, by increasing FcRgammaIII(+) natural killer (NK) cell numbers and cytolytic function in vivo, when added to trastuzumab, can increase efficacy, be safely given, and avoid the use of chemotherapy. Experimental Design: In this Phase I trial, 10 patients with HER2-overexpressing metastatic breast cancer were treated with IL-2 (1.75 x 10(6) IU/m(2)/day, s.c.) for 7 weeks and trastuzumab (4 mg/kg load and then 2 mg/kg weekly) for 6 weeks. Safety, in vitro immune responses, and clinical responses were assessed. RESULTS: Ten women received a total of 12 cycles of therapy (each cycle lasted 7 weeks). No significant toxicities were seen, and one patient required an IL-2 dose reduction. Among the evaluable patients (10 cycles), the responses were one partial response, five cases of stable disease, and four cases of progressive disease. In vitro immune assays showed NK cell expansion and trastuzumab-mediated increased NK cell killing of breast cancer targets (antibody-dependent cellular cytotoxicity) in a HER2-specific manner but did not correlate with clinical responses. CONCLUSIONS: Trastuzumab + IL-2 is a well-tolerated outpatient regimen that results in NK cell expansion with enhanced in vitro targeted killing of HER2-expressing cells. These preliminary data suggest that this strategy may benefit heavily pretreated metastatic breast cancer patients.     

Preoperative and postoperative cytokines in patients with cancer.

BACKGROUND. Changes in tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and granulocyte macrophage-colony-stimulating factor (GM-CSF) were investigated before and after operation in patients with hepatocellular carcinoma (HCC), metastatic liver carcinoma, and gastrointestinal carcinoma. RESULTS. Serum levels of TNF-alpha, IL-1 alpha, and IL-1 beta were high in patients with liver carcinoma (HCC and metastatic liver carcinoma) before operation in comparison with those of normal controls (P less than 0.01). In patients with gastrointestinal carcinoma, serum levels of cytokines, except those of TNF-alpha, were the same as in patients with liver carcinoma. The level of TNF-alpha in patients with gastrointestinal carcinoma was low compared with that in patients with liver carcinoma. Within 1 day after operation, the peak level of TNF-alpha was observed at 15 hours, IL-1 alpha at 18 hours, IL-1 beta at 21 hours, and IL-6 at 24 hours after operation. Subsequently, these cytokine levels peaked again: TNF-alpha at 48 hours, IL-1 alpha at 72 hours, IL-1 beta at 120 hours, and IL-6 at 168 hours after operation. GM-CSF levels increased gradually after operation. Moreover, in HCC, serum levels of TNF-alpha were high in patients with recurrence compared with those without recurrence (P less than 0.01). The difference in IL-1 alpha and IL-1 beta levels between patients with recurrence and those without recurrence can be regarded as significant (P less than 0.01). CONCLUSION. These results suggest that TNF-alpha, IL-1, IL-6, and GM-CSF may play an important role in the pathogenesis of cancers; TNF-alpha may be especially important as a tumor marker in HCC and metastatic liver carcinoma.     

Esorubicin (4'-deoxydoxorubicin, NSC 267469) in advanced breast cancer. A phase II study of the CALGB

Forty-six eligible women with advanced metastatic breast cancer were entered on a Phase II trial utilizing esorubicin (4'-deoxydoxorubicin) given in a dosage of 30 mg/m2 intravenously every 3 weeks. No patient had received anthracyclines or cytotoxic therapy for metastatic disease. Twenty-three (50% of patients) had prior adjuvant chemotherapy, 21 (46%) had prior hormonal therapy, and 32 (70%) were postmenopausal. Dominant site of disease was visceral in 26 (57%), bone in 14 (30%), and soft tissue in 6 (13%). There were 3 complete and 13 partial responders observed, for a 35% response rate; 95% confidence interval for response was 21-49%. Median response duration was 4.0 months (range 2-21 months), and one partial responder remains on study at 6.3 months. Thirty-nine of 46 patients have died; median survival was 10.1 months. Toxicity was primarily hematologic, with 2 drug-related septic deaths. In addition, 2 patients developed severe congestive heart failure secondary to esorubicin cardiotoxicity (at 687 and 770 mg/m2, respectively), which resulted in one patient death. Nausea and vomiting were severe in 16% of patients, but total alopecia was only noted in 4 (9%). Esorubicin is an active agent in metastatic breast cancer; its role in treatment remains undefined.     

A Phase I study of docetaxel plus cyclophosphamide in solid tumors followed by a Phase II study as first-line therapy in metastatic breast cancer.

PURPOSE: In Phase I, the purpose was to determine the maximum tolerated dose and pharmacokinetics of docetaxel plus cyclophosphamide (DC) with and without granulocyte colony-stimulating factor in the treatment of patients with solid tumors. For Phase II, the purpose was to determine the safety and efficacy of this combination as first-line treatment in patients with metastatic breast cancer (MBC). EXPERIMENTAL DESIGN: In Phase I (45 patients), docetaxel was escalated from 60 mg/m(2) to 85 mg/m(2), and cyclophosphamide from 600 mg/m(2) to 800 mg/m(2). Pharmacokinetic evaluation of docetaxel was performed in 19 patients with MBC. In Phase II (34 patients), patients received cyclophosphamide (600 mg/m(2)) followed by docetaxel (75 mg/m(2)), i.v. RESULTS: In Phase I, the dose-limiting toxicity was neutropenia-related events. The maximum tolerated dose for DC was 75 mg/m(2)/700 mg/m(2) in solid tumor patients treated previously and 75 mg/m(2)/800 mg/m(2) for patients not treated previously for MBC. Dose escalation of docetaxel >75 mg/m(2) was not tolerated, despite prophylactic granulocyte colony-stimulating factor treatment. In Phase II, 71% of patients received prior anthracycline therapy. Neutropenic fever requiring i.v. antibiotics occurred in 6 patients (19%). One patient had grade 3 neuropathy. There was no cardiotoxicity. The overall Phase II intent-to-treat objective response rate was 65% (complete responses, 12%). The median overall survival was 22 months, and the median time to progression was 6 months. CONCLUSIONS: DC combination therapy is an active regimen with acceptable toxicity and is appropriate regardless of prior anthracycline therapy. In view of the high activity and lack of cardiotoxicity, this combination warrants additional investigation in early stage breast cancer and in combination with trastuzumab.     

In Vitro Effects of Lithium Chloride on TNFα and IL-6 Production by Monocytes from Breast Cancer Patients

Abstract

It is well known that lithium chloride (LiCI) is able to trigger human monocytes to release tumor necrosis factor alpha (TNFα). In this study we have evaluated the In Vitro effect of LiCI on TNFα and interleukin-6 (IL-6) release by monocytes from patients affected by non-metastatic (BCa/M0) and metastatic breast cancer (BCa/M1), preincubated with autologous serum (sPt). Our data demonstrate that monocytes from cancer patients (BCa) treated with LiCI released lower amounts of TNFα compared to those from healthy donors (HD). Preincubation in autologous serum (sPt) impaired TNFα production by monocytes treated with LiCI. On the contrary, our data indicate that IL-6 production by monocytes from BCa was not impaired. Moreover, the results obtained from the same cells, preincubated in sPt and treated with LiCl, indicate that serum factors may synergize with LiCI treatment in releasing IL-6.     

卡培他滨治疗蒽环类及紫杉类耐药的复发转移性乳腺癌的临床观察

目的:观察卡培他滨对蒽环类、紫杉类耐药的复发转移性乳腺癌的作用。方法:40例复发转移性乳腺癌患者,均经过蒽环类及紫杉类治疗后出现疾病进展。给予卡培他滨2510mg/(m2·d),分2次口服,连服2周,3周为1个周期。至少2个周期后评价疗效。结果:本组化疗均数为4个周期。CR1例,PR8例,SD23例,PD7例,有效率23.1%,疾病控制率(CR PR SD)为82.0%(32/39);TTP3.4个月;中位生存时间11.2个月。常见不良反应为手足综合征(70.0%)、皮肤色素沉着(60.0%)、恶心呕吐(52.5%)、腹泻(42.5%),2例出现3～4级严重腹泻而住院治疗。结论:卡培他滨对蒽环类、紫杉类耐药的复发转移性乳腺癌仍有一定的疗效,耐受性较好。     

Epirubicin-vinorelbine intravenous combination followed by oral vinorelbine as first-line treatment in metastatic breast cancer

Epirubicin and vinorelbine are considered active drugs in metastatic breast cancer. The optimal duration of a chemotherapy regimen for metastatic breast cancer patients is still unknown. Nevertheless, epirubicin has a dose-limiting cardiotoxicity. Vinorelbine is also available as oral formulation. In a multicenter phase II study, we analyzed the feasibility and the efficacy of a maximum of six cycles of i.v. epirubicin plus vinorelbine, followed by oral vinorelbine. We enrolled 30 patients with metastatic breast cancer. Each patient received epirubicin (75 mg/m2 on day 1) and vinorelbine (25 mg/m2 on days 1-8), every 3 weeks, for three cycles or six cycles in case of objective response or stable disease. When a clinical benefit was obtained, patients received oral vinorelbine (60 mg/m2 on days 1-8 every 3 weeks for three cycles). The regimen demonstrated to be active and well tolerated in metastatic breast cancer, and 6-8 months represented the optimal treatment duration. Maintenance therapy with oral vinorelbine was feasible, effective, safe and well accepted by the patients.     

Tumor necrosis factor‐α induces prostate cancer cell migration in lymphatic metastasis through CCR7 upregulation

Understanding the mechanism of lymph node metastasis, a poor prognostic sign for prostate cancer, and the further dissemination of the disease is important to develop novel treatment strategies. Recent studies have reported that C‐C chemokine receptor 7 (CCR7), whose ligand is CCL21, is abundantly expressed in lymph node metastasis and promotes cancer progression. Tumor necrosis factor‐α (TNF‐α) is chronically produced at low levels within the tumor microenvironment. The aim of this study was to determine whether TNF‐α promotes prostate cancer dissemination from metastatic lymph nodes through activation of the CCL21/CCR7 axis. First, human prostate cancer cells were determined to express both TNF‐α and CCR7. Second, low concentrations of TNF‐α were confirmed to induce CCR7 in prostate cancer cells through phosphorylation of ERK. Finally, CCL21 was found to promote the migration of prostate cancer cells through phosphorylation of the protein kinase p38. Our results suggest that TNF‐α leads to the induction of CCR7 expression and that the CCL21/CCR7 axis might increase the metastatic potential of prostate cancer cells in lymph node metastasis.     

曲妥珠单抗联合多西紫杉醇治疗Her-2/neu高表达转移性乳腺癌的疗效和不良反应

背景与目的:大约有20%～30%的乳腺癌患者Her-2/neu高表达,Her-2/neu高表达与患者的不良预后密切相关.化疗药物联合曲妥珠单抗可以显著提高Her-2/neu高表达乳腺癌患者的化疗有效率和生存率,多西紫杉醇是近年来治疗乳腺癌有效的化疗药物之一.本研究旨在观察曲妥珠单抗联合多西紫杉醇治疗Her-2/neu高表达转移性乳腺癌的疗效与不良反应.方法:22例Her-2/neu高表达转移性乳腺癌患者接受曲妥珠单抗联合多西紫杉醇方案治疗,曲妥珠单抗的首次剂量为8 mg/kg,以后的剂量为6 mg/kg.多西紫杉醇75mg/m2,每21 d重复一次.按WHO疗效评价标准评价疗效,按WHO化疗药物急性和亚急性不良反应评价标准评价不良反应.结果:全组22例患者共完成96个周期化疗(中位数3周期,范围2～6周期),所有患者均可评价疗效.22例患者中完全缓解2例,部分缓解12例,病情稳定4例,病情进展4例,客观有效率(CR PR)63.64%,中位疾病进展时间5.4个月,1年生存率59%.全组患者均可评价不良反应,主要不良反应为骨髓抑制,其中Ⅲ～Ⅳ度白细胞减少发生率为54.5%,部分患者有发热(第一次输注曲妥珠单抗时出现)和轻度的心肌劳损.结论:曲妥珠单抗联合多西紫杉醇方案治疗Her-2/neu高表达转移性乳腺癌近期疗效较高,不良反应轻,患者可以耐受.     

Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits.

BACKGROUND: Bortezomib (VELCADE) is a potent inhibitor of the 26S proteasome with broad antitumor activity. We performed a phase II study of bortezomib to evaluate its clinical effects in patients with metastatic breast cancer. PATIENTS AND METHODS: Twelve patients with metastatic breast cancer were treated with bortezomib (VELCADE) at a dosage of 1.5 mg/m(2) administered biweekly for 2 weeks with 1 week of rest in a 21-day cycle. The primary objective was clinical response rate. Toxicity and pharmacodynamics data were also obtained. RESULTS: No objective responses were observed. One patient had stable disease, and 11 others experienced disease progression. The median survival time was 4.3 months (range, 0.9-37 months). The most common grade 3 or 4 toxicities included fatigue (58%; n = 7) and skin rash (33%; n = 4). The mean inhibition of specific chymotryptic activity was 53.1% (+/- 13.33%). A statistically significant reduction in the plasma interleukin-6 level was seen (P = 0.0354). CONCLUSION: Bortezomib was well tolerated but showed limited clinical activity against metastatic breast cancer when used as a single agent. The future development of this agent for the treatment of breast cancer should be guided by in vivo models that optimize activity in combination with other antitumor agents.