DHAOx方案治疗难治性或复发性非霍奇金淋巴瘤的临床观察

目的:观察DHAOx方案治疗难治性或复发性非霍奇金淋巴瘤的临床疗效及毒副反应。方法:21例患者接受DHAOx方案(奥沙利铂(L-OHP)130mg.m-2静脉滴入3h,d1;阿糖胞苷(Ara-C)2g.m-2静脉滴入,d2,每12h1次;地塞米松(DXM)20～40mg.d-1静脉滴入,d1～4;21～28d为1个周期)治疗。2周期后评价疗效和毒副反应。结果:完全缓解4例(19.0%),部分缓解8例(38.1%),疾病稳定6例(28.6%),疾病进展3例(14.3%),总有效率为57.1%。主要毒副反应为:Ⅲ～Ⅳ级中性粒细胞下降占33.3%(7/21);Ⅲ～Ⅳ级血小板下降占14.3%(3/21);Ⅰ～Ⅱ级腹泻33.3%(7/21),Ⅲ～Ⅳ级腹泻4.8%(1/21);Ⅰ～Ⅱ度外周神经毒性占81.0%(17/21),无Ⅲ～Ⅳ级外周神经毒性发生;Ⅰ～Ⅱ级恶心、呕吐38.1%(8/21),无Ⅲ～Ⅳ级恶心、呕吐反应;Ⅰ～Ⅱ级肝功能损害19.0%(4/21),无肾功能损害及Ⅲ～Ⅳ级肝功能损害。结论:DHAOx方案治疗难治性或复发性非霍奇金淋巴瘤有效性较高,毒副反应可耐受。     

A Phase I Clinical and Pharmacokinetic Study of Fenretinide Combined with Paclitaxel and Cisplatin for Refractory Solid Tumors

Summary Background: Fenretinide is a semi-synthetic retinoid that has pro-apoptotic effects as a single agent and synergistically with chemotherapy in vitro. We performed this study to determine the toxicity of cisplatin, paclitaxel and fenretinide in patients with advanced cancer, the recommended phase II dose of these agents together, and the pharmacokinetics (PK) of fenretinide when administered with chemotherapy. Patients and methods: Fourteen patients (mean age 57.3) were assessable for pharmacokinetics, toxicity and response. Fenretinide was given orally in 2 divided daily doses for 7 days, starting 24 hours prior to cisplatin and paclitaxel. Cisplatin and paclitaxel were given in standard fashion. Cycles were repeated every 3 weeks. Cycle one fenretinide PK was obtained on days 2 and 8. Results: Dose limiting toxicity (Gr 3 diarrhea and Gr 4 neutropenia) was encountered in two patients during cycle one at 80/175/1800 mg/m² of cisplatin/paclitaxel/fenretinide (dose level 2), respectively. Seven patients received 2–8 cycles at the recommended level of 60/135/1800 (dose level 1). Severe cumulative toxicities included fatigue, nausea/vomiting, neuropathy, and dehydration. Two patients had a partial response and 4 patients had stable disease for up to 8 cycles. PK analysis demonstrated a reduction in fenretinide Cmax on day 8 compared to day 2, accompanying a decrease in AUC. Conclusions: Cisplatin/paclitaxel/fenretinide can be administered safely at 60/135/1800 mg/m² respectively on an every three-week schedule. This combination may have activity in a variety of tumors, however, the number of pills required complicates oral dosing of fenretinide, and limits the applicability of this regimen.     

Treatment of AIDS Related Non-Hodgkin's Lymphoma with Combination Mitoguazone Dihydrochloride and Low Dose Chop Chemotherapy: Results of a Phase II study

PURPOSE: To evaluate the response and side effects of combination therapy with low dose CHOP chemotherapy and mitoguazone dihydrochloride in patients with non-Hodgkin's lymphoma associated with the acquired immunodeficiency syndrome (AIDS-NHL). METHODS: Eighteen patients newly diagnosed with intermediate or high-grade AIDS-NHL were treated with low dose CHOP as follows: day 1, cyclophosphamide 350 mg/m(2), intravenously (IV); doxorubicin 25mg/m(2) IV; vincristine 2mg IV; and prednisone 100mg given orally on days 1 through 5. In addition, mitoguazone dihydrochloride was given at a dose of 600 mg/m(2) IV on days 1 and 15 of each 28-day treatment cycle. RESULTS: Seventeen males and one female patient were accrued. Twelve patients had high-grade pathologies while the remainder had an intermediate grade pathology (diffuse large cell). The median CD4+ lymphocyte count was 98/dl (range 1-924). Three patients (17%) reported an AIDS-defining illness prior to lymphoma diagnosis. Of 14 evaluable patients, 6 (43%) achieved a complete remission and 5 (35%) a partial remission. The median failure free and overall survival times were 6.5 and 8.4 months, respectively. Major toxicity was hematologic with grade 3 or 4 neutropenia in 72%; two patients died of neutropenic sepsis. CONCLUSIONS: Mitoguazone in combination with low dose CHOP is a safe regimen, associated with a response rate of 79% (CR 43%, PR 36%, 95% CI=49-95%). These preliminary results suggest no major improvement in terms of response over use of CHOP without mitoguazone.     

Gemcitabine and Cisplatin for Patients with Metastatic or Recurrent Esophageal Carcinoma: A Southwest Oncology Group Study

PURPOSE: Experimental data, both in vivo and in vitro, suggest that the combination of gemcitabine and cisplatin acts synergistically. Within the Southwest Oncology Group, we designed a Phase II trial to test this chemotherapy combination for patients with esophageal cancer. EXPERIMENTAL DESIGN: Patients with metastatic or recurrent esophageal cancer were treated with gemcitabine 1000 mg/m(2) on days 1, 8, and 15, and cisplatin 100 mg/m(2) on day 15. Cycles were repeated every 28 days. The statistical endpoint was overall survival. RESULTS: Sixty-four eligible patients were accrued from 37 institutions. Twenty-six percent of patients had prior chemotherapy. The treatment was generally well-tolerated, with the most common toxicity being neutropenia in 31% of patients. All 64 patients have died. Survival at 3 months was 81%, and at 1 year was 20%. Median survival was 7.3 months. CONCLUSIONS: This regimen is tolerable palliative option for patients with metastatic esophageal cancer.     

Phase II Trial of Pyrazoloacridine as Second-Line Therapy for Patients with Unresectable or Metastatic Transitional Cell Carcinoma

Purpose: A phase II trial of pyrazoloacridine(PZA) was conducted to assess its activity andtoxicity in patients with advanced transitional cellcarcinoma (TCC) refractory to or progressing after oneprior cisplatin-, carboplatin- or paclitaxel- basedregimen. Patients and methods: PZA at a dose of750 mg/m² was administered to 14 patients as athree-hour intravenous infusion on day 1 every 21days. Premedication consisted of lorazepam 0.5-1.0 mgprior to each cycle to alleviate central nervoussystem toxicity. Reduction of subsequent doses wasmade for hematologic or central nervous systemtoxicity. Results: Among fourteen patients evaluable forresponse, no responses were observed (0% responserate; 95% confidence interval 0% to 23%). Themedian duration of survival for all patients was 9months with a median follow-up of 8.5 months. Toxicityto PZA included grade 3 or 4 neutropenia in 8/14(57%) and grade 3 or 4 thrombocytopenia in 2/14(14%). Non-hematologic toxicity was mild. Conclusions: PZA at this dose and schedule does nothave significant single-agent acitvity in patientswith TCC who have failed one prior regimen.     

Phase II Study of CI-958 in Patients with Hormone Refractory Prostate Carcinoma

A phase II trial of CI-958 (NSC #635371), a new benzothiopyranoindazole was performed in patients with hormone refractory prostate carcinoma using prostate specific antigen (PSA) levels for response assessment. Twenty-two patients were entered on this study and twenty one were eligible. Toxicity consisted mainly of granulocytopenia (71% grade 3 or 4), but there were no significant infections. Two patients were removed from study due to asymptomatic decreases in cardiac ejection fraction. Of 21 evaluable patients, there were four responders (19%, CI 0-35%).     

A Phase II Study of 9-Nitro-Camptothecin in Patients with Previously Treated Metastatic Breast Cancer

AIMS: This Phase II study was conducted to determine the efficacy and toxicity of 9-nitro-camptothecin (9-NC) in patients with previously treated metastatic breast cancer. Pharmacokinetic samples were obtained to investigate the correlation of plasma 9-NC exposure with clinical response and toxicity. PATIENTS AND METHODS: Eligible patients had histologically confirmed metastatic breast cancer with measurable or evaluable disease. Patients must have received one or two prior chemotherapy regimens for metastatic disease. 9-NC was given orally, 1.5 mg/m(2)/day for 5 days each week; response was assessed every 8 weeks. Pharmacokinetic samples were obtained on day 1 of weeks 1 and 5. RESULTS: Eighteen patients were enrolled between September 1999 and May 2000; seventeen patients were evaluable for response. The most common toxicities were nausea, vomiting, urinary symptoms, fatigue and diarrhea. No objective responses were observed; six patients had stable disease. 9-NC apparent clearance ranged from 0.57 to 55.08 L/h (median 5.91 L/h); 9-NC area under the curve ranged from 38 to 2130 ng/ml x h (median 377 ng/ml x h). There was no relationship between pharmacokinetic parameters and individual patient toxicity. CONCLUSION: 9-NC has limited activity in patients with previously treated metastatic breast cancer. Though 9-NC has substantial pharmacokinetic variability in this patient population; no correlation was found between pharmacokinetic variables and toxicity.     

Phase II Clinical Trial of Didemnin B in Patients with Recurrent or Refractory Anaplastic Astrocytoma or Glioblastoma Multiforme (NSC 325319)

The activity of didemnin B, a natural product derived from the Caribbean Tunic was assessed in 16 patients with Glioblastoma multiforme. Didemnin B was administered intravenously by a short infusion at a dose of 4.3 mg/m² and subsequently escalated to 6.3 mg/m². No anti-tumor activity was observed. Toxicity consisted of fatigue, weakness, stomatitis, mild blood count changes, nausea and vomiting and occasional fever. Based on these results further studies with didemnin B in patients with Glioblastoma multiforme are not recommended.     

A Randomized Trial Comparing the Nephrotoxicity of Cisplatin/Ifosfamide-Based Combination Chemotherapy with or without Amifostine in Patients with Solid Tumors

This study evaluates the degree of kidney damageduring cisplatin/ifosfamide-based combinationchemotherapy and its possible prevention byamifostine. Thirty-one patients with solid tumorsstratified according to pretreatment were randomizedto receive VIP- or TIP-chemotherapy with or withoutamifostine (910 mg/m²) given as a short infusion priorto cisplatin. Chemotherapy consisted of cisplatin(50 mg/m²), ifosfamide (4 g/m²) and either etoposide(500 mg/m²) (= VIP) or paclitaxel (175 mg/m²) (= TIP)repeated at 3 weekly intervals. For all patients theglomerular filtration rate (GFR) measured bycreatinine-clearance, serum creatinine, electrolytesand differential urinary protein/enzyme excretion weredetermined prior to, during and after each cycle. Atotal of 62 cycles of chemotherapy were evaluable. Inthe amifostine-group GFR was fully maintained afterapplication of two cycles of chemotherapy, whereas inthe control group a > 30%-reduction of median GFR(108 to 80 ml/min) was observed (p < 0.001). Patientsreceiving amifostine had a lower degree of highmolecular weight proteins excretion indicating lessglomerular damage. In both groups significantincreases of tubular marker profiles peaking at day 3after chemotherapy were observed with a nearlycomplete reversibility of these changes prior to thenext chemotherapy cycle. The number of patients withlow magnesium serum levels during treatment was 17%after amifostine application versus 69% in controlpatients. The results seem to indicate that treatmentwith amifostine can preserve GFR after application oftwo cisplatin/ifosfamide-based chemotherapy cycles.This may be advantageous if repetitive cycles ofchemotherapy or subsequent administration of high dosechemotherapy is planned.     

异甘草酸镁与多烯磷脂酰胆碱预防化疗药物致非霍奇金淋巴瘤患者肝损伤的药物经济学研究

目的：观察异甘草酸镁与多烯磷脂酰胆碱对化疗药物所致非霍奇金淋巴瘤（NHL）患者急性药物性肝损伤的预防作用,并作药物经济学评价。方法：运用回顾性分析方法,选择2014年1月至2018年10月病理诊断为非霍奇金淋巴瘤的患者184例,分为异甘草酸镁组、多烯磷脂酰胆碱组。化疗方案分别采用CHOP方案、R-CHOP方案。观察患者化疗前后肝功能生化指标,统计患者住院期间保肝药物费用,对两种保肝方案作疗效和药物经济学评价。结果：两种保肝方案在预防NHL患者所致肝损伤疗效上无显著性差异（P>0.05）,最小成本分析结果显示,多烯磷脂酰胆碱的经济性较好。结论：两种保肝方案均能有效地预防化疗所致肝损伤,但多烯磷脂酰胆碱价格便宜,在经济性上具有明显优势。     

替莫唑胺联合伊立替康治疗复发性非小细胞肺癌脑转移的疗效和毒副作用分析

目的:评价替莫唑胺联合伊立替康治疗复发性非小细胞肺癌(NSCLC)脑转移的疗效及毒副反应。方法:对20例既往至少经一线化疗方案治疗和(或)全脑放射治疗后未达缓解或缓解后复发的患者给予替莫唑胺每天150²00mg·m-2,第1天200mg·m-2,第1天^第5天,伊立替康60 mg?m-2,iv,第1、8天,21d为1周期,最多化疗6周期。结果:20例患者中,男性12例(60.0%),女性8例(40.0%),中位年龄为54岁,ECOG评分≤1分,治疗周期数1第5天,伊立替康60 mg?m-2,iv,第1、8天,21d为1周期,最多化疗6周期。结果:20例患者中,男性12例(60.0%),女性8例(40.0%),中位年龄为54岁,ECOG评分≤1分,治疗周期数1⁶周期,中位治疗3周期。其中2例部分缓解,近期有效率10%,4例稳定(20.0%),14例进展(70.0%)。毒副反应可耐受,最常见的不良反应是骨髓抑制和胃肠道反应。骨髓抑制主要表现为:白细胞(WBC)或中性粒细胞(NEUT)下降20例(100%),其中I6周期,中位治疗3周期。其中2例部分缓解,近期有效率10%,4例稳定(20.0%),14例进展(70.0%)。毒副反应可耐受,最常见的不良反应是骨髓抑制和胃肠道反应。骨髓抑制主要表现为:白细胞(WBC)或中性粒细胞(NEUT)下降20例(100%),其中I^II度14例(70.0%),III度5例(25.0%),IV度1例(5.0%);胃肠道反应较轻微,主要为III度14例(70.0%),III度5例(25.0%),IV度1例(5.0%);胃肠道反应较轻微,主要为I^II度15例(75.0%)。其余较常见的毒副反应还包括腹泻5例(25.0%),其中I度4例(20.0%),II度1例(5.0%),肝功能损害3例,均为I度(15.0%)。结论:替莫唑胺联合伊立替康治疗复发性NSCLC脑转移的化疗疗效良好,毒副反应轻微。     

Phase II Trial of Aminocamptothecin (9-AC/DMA) in Patients with Advanced Squamous Cell Head and Neck Cancer

Fourteen patients with squamous cell carcinoma of the head and neck received 9-AC/DMA infusions of 850 mg/M²/day over 72 hours. Eligibility criteria included good performance status, advanced disease incurable by conventional means, no prior treatment of metastatic disease, and measurable lesions for objective response assessment. The infusions wererepeated at 21 day intervals until progression or prohibitive toxicity occurred.A median of 3 cycles (range 1–7) was given. No objective responses wereobserved. Median survival of the group was 6 months. Toxicity was hematologicwhich was modest and promptly reversible. 9-AC/DMA is inactive against this tumortype at the dose and schedule employed in this study.     

A Phase I Trial of Cisplatin Plus Decitabine, a New DNA-Hypomethylating Agent, in Patients with Advanced Solid Tumors and a Follow-Up Early Phase II Evaluation in Patients with Inoperable Non-Small Cell Lung Cancer

The authors describe a phase I trial of cisplatin plusdecitabine, a novel DNA-hypomethylating agent, in patients withadvanced solid tumors, which was followed by an early phase IIevaluation of the combination in patients with inoperablenon-small cell lung cancer (NSCLC). In the phase I trial,cisplatin was studied at a fixed dose of 33 mg/m²,while decitabine was escalated in four (I–IV) doseescalation levels (45, 67, 90 to 120 mg/m²,respectively) in consecutive groups of at least 3 patients perdose level. Decitabine was administered to the patients as atwo-hour intravenous infusion, while cisplatin was givenintravenously immediately after the end of decitabine infusion.Both agents were given on days 1–3 every 21 days.Twenty-one patients were included in the phase trial. Dose levelIV (120 mg/m² decitabine) was considered the maximumtolerated dose (MTD), while the dose-limiting toxicities wereneutropenia, thrombocytopenia and mucositis. The recommendeddoses for phase II trials in good- and poor-risk patients were90 (level III) and 67 mg/m² (level II), respectively.One short-lasting partial response was observed in a patient withcervical cancer, while two minor regression were documented ina patients with NSCLC and cervical cancer, respectively. Doselevel II was selected for the phase II trial in patients withinoperable NSCLC. Fourteen consecutive patients were included inthis part of the study. The median age of the patients was 57years (range, 39–75), male/female ratio of –11/3 anda median WHO performance status 1 (0–2). The stage ofdisease were IIIB (5) and IV (9). Prior irradiation to the chestwas given in one case. A total of 30 treatment courses wereevaluable for toxicity and response, with a median of 2 coursesper patient (1–4). Grade 3–4 neutropenia andthrombocytopenia were observed in about half of the cases.Mucositis, diarrhea, nausea and vomiting, and skin rash were alsoobserved in some patients. Three minor responses were documented,which lasted for 4, 16 and 36 weeks. Median survival of patientswas 15 weeks (4–38). In conclusion, the cisplatin plusdecitabine combination did not exhibit significant antitumoractivity in patients with NSCLC at the dose and schedule appliedin this trial to justify its further evaluation in this patientpopulation.     

A Phase II Trial of Etoposide, Leucovorin, 5-FU, and Interferon Alpha 2b (ELFI) + G-CSF for Patients with Pancreatic Adenocarcinoma: a Southwest Oncology Group Study (SWOG 9413)

Background. Chemotherapeutic treatments using combinationsof etoposide, leucovorin and 5-FU (ELF) have shown activity inthe treatment of gastrointestinal malignancies. Interferon alpha2b is known to have antiproliferative effects on several celllines and has well documented in vitro evidence ofsynergism with 5-FU. It was postulated that the combination ofELF and interferon alpha 2b would improve response rates andsurvival in patients with pancreas cancer. Methods. Fifty-five eligible patients with locally-advancedor metastatic pancreatic adenocarcinoma received a regimenconsisting of: IV leucovorin at 300 mg/m²/day on Days 1-3(of 28-day cycle), IV etoposide at 80 mg/m²/day on Days 1-3, IV 5-FU at 500 mg/m²/day on Days 1-3, subcutaneousinterferon alpha 2b at 3 million units TIW, and subcutaneousG-CSF at 5 g/kg/day on Days 4-14 (or until WBC exceeds10,000/l). Patients with no evidence of disease progressioncontinued on treatment for a total of 6 cycles. Results. Complete response was demonstrated in 1 patient,partial response in 5 patients (11% confirmed response rate).The median survival was 5 months, and the six-month survival ratewas 40%. Ten patients completed all 6 cycles of treatment.Toxicity-related dose delays and reductions were necessary formost patients. Conclusions. Although the combination of ELF and interferonalpha 2b (ELFI) has modest activity in pancreatic cancer, it isa toxic and complex regimen that is not superior to othercurrently available approaches for the chemotherapeuticmanagement of pancreatic cancer. ELFI cannot be recommended asa standard therapy.     

A Phase II Study of Intravenous Exatecan Mesylate (DX-8951f) Administered Daily for Five Days Every Three Weeks to Patients with Metastatic Adenocarcinoma of the Colon or Rectum

BACKGROUND: To evaluate the antitumor activity, toxicities, and pharmacokinetics (PK) of DX-8951f administered as a 30-min infusion daily for 5 days every 3 weeks in patients with fluorouracil-resistant metastatic colorectal carcinoma. PATIENTS AND METHODS: Sixteen patients were enrolled. All had metastatic colorectal carcinoma resistant to or progressing after chemotherapy containing 5-fluorouracil and no prior chemotherapy with camptothecin derivatives. DX-8951f was administered until disease progression or unacceptable toxicity. Responses were assessed after every two courses. RESULTS: Fifteen patients were evaluable. Fifty-one courses of therapy were delivered (median 2). Responses were one minor response, six stable disease, and eight progressive disease. The principal adverse event was neutropenia, with grade 3 and 4 toxicities in three and eight patients, respectively. Non-hematologic toxicities were mild to moderate; the most common were fatigue, nausea, and diarrhea. Plasma concentrations of DX-8951 were well described using a linear two-compartment PK model. There was no evidence of nonlinearity in the elimination of PK or auto-inhibition or induction of DX-8951 clearance over the 5 days of administration. CONCLUSIONS: DX-8951f at this dose and schedule had no significant activity in this patient population. The toxicity profile, mainly hematologic, was consistent with previous reports. The clearance and volume of distribution were not different from those previously reported.     

A Phase I/II study of docetaxel, etoposide, and carboplatin before concurrent chemoradiotherapy with cisplatin and etoposide in limited-stage small cell lung cancer

Summary Limited stage small cell lung cancer (LS-SCLC) is an infrequent but aggressive tumor. No major advances in the treatment of this disease have been achieved in recent years. This study was conducted to determine the maximum-tolerated dose (MTD) and efficacy of docetaxel, etoposide, and carboplatin (DEC) given before definitive chest radiotherapy with concurrent cisplatin and etoposide. Seventeen untreated LS-SCLC patients received docetaxel 50 mg/m², etoposide 50–80 mg/m², and carboplatin AUC = 5–6, intravenously on day 1 followed by etoposide 100–160 mg/m² orally on days 2 and 3 every 21 days for two cycles followed by once daily radiotherapy to a total dose of 50 Gy given concurrently with cisplatin (60 mg/m², d1) and etoposide (120 mg/m², d1 and 240 mg/m² day 2–3) for 2 cycles. All patients were assessable for toxicity and 15 for response. The most frequent toxicity was grade 3 and 4 neutropenia in 41% of patients during DEC and in 57% with chemoradiation. The MTD for DEC was docetaxel 50 mg/m² plus carboplatin AUC = 5 and etoposide 50/100 mg/m² with growth factor support. Significant nonhematologic toxicities were primarily radiation-related esophagitis (43%). One patient (6%) died from toxicity. The overall response rate was 82% with 10 patients (59%) achieving a complete response. The median survival was 12.1 months (95% CI, 6.4–17.8 months) and the 1-year survival rate was 47%. This novel approach produced similar efficacy results to current two drug regimens but was associated with significant neutropenia. Alternative strategies to increase complete response rates and survival are needed.     

Effects on G2/M Phase Cell Cycle Distribution and Aneuploidy Formation of Exposure to a 60 Hz Electromagnetic Field in Combination with Ionizing Radiation or Hydrogen Peroxide in L132 Nontumorigenic Human Lung Epithelial Cells

The aim of the present study was to assess whether exposure to the combination of an extremely low frequency magnetic field (ELF-MF; 60 Hz, 1 mT or 2 mT) with a stress factor, such as ionizing radiation (IR) or H₂O₂, results in genomic instability in non-tumorigenic human lung epithelial L132 cells. To this end, the percentages of G2/M-arrested cells and aneuploid cells were examined. Exposure to 0.5 Gy IR or 0.05 mM H₂O₂ for 9 h resulted in the highest levels of aneuploidy; however, no cells were observed in the subG1 phase, which indicated the absence of apoptotic cell death. Exposure to an ELF-MF alone (1 mT or 2 mT) did not affect the percentages of G2/M-arrested cells, aneuploid cells, or the populations of cells in the subG1 phase. Moreover, when cells were exposed to a 1 mT or 2 mT ELF-MF in combination with IR (0.5 Gy) or H₂O₂ (0.05 mM), the ELF-MF did not further increase the percentages of G2/M-arrested cells or aneuploid cells. These results suggest that ELF-MFs alone do not induce either G2/M arrest or aneuploidy, even when administered in combination with different stressors.     

Incidence of and Risk Factors for Severe Adverse Events in Elderly Patients Taking Angiotensin‐Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers after an Acute Myocardial Infarction

Study Objective

To assess the incidence of and risk factors associated with severe adverse events in elderly patients who used angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) after an acute myocardial infarction (AMI).

Design

Retrospective cohort study.

Data Sources

Centers for Medicare & Medicaid Services Chronic Conditions Data Warehouse (Medicare service claims database), American Community Survey of the U.S. Census Bureau, and Multum Lexicon Drug database.

Patients

A total of 101,588 eligible Medicare fee‐for‐service beneficiaries 66 years or older, who were hospitalized for AMI between January 1, 2008, and December 31, 2009, and used ACEIs or ARBs within 30 days after discharge.

Measurements and Main Results

Primary outcomes were hospitalizations for acute renal failure (ARF) and hyperkalemia. The secondary outcome was discontinuation or suspension of ACEI/ARB therapy after a visit to a health care provider. The primary risk factors of interest were age, sex, race/ethnicity, and chronic kidney disease (CKD). Cumulative incidence curves and multivariable Fine‐Gray proportional hazards models with 95% confidence intervals (CIs) were used with death as a competing risk in both intention‐to‐treat (ITT) and as‐treated (AT) analyses. In the study cohort, 2.8% experienced ARF, 0.5% experienced hyperkalemia, and 63.7% discontinued ACEI/ARB therapy within 1 year after hospital discharge. Approximately half of the incidence of ARF and hyperkalemia occurred within 6 months after hospital discharge, but the cumulative incidence increased after 6 months. Patients older than 85 years had a higher rate of ARF (ITT hazard ratio [HR] 1.15, 95% CI 1.04–1.28) and hyperkalemia (ITT HR 1.33, 95% CI 1.05–1.68) compared with those aged 65–74 years. Patients with baseline CKD had higher rates of ARF (ITT HR 1.61, 95% CI 1.42–1.82), hyperkalemia (ITT HR 1.41, 95% CI 1.11–1.77), and ACEI/ARB therapy discontinuation or suspension (ITT HR 1.05, 95% CI 1.02–1.09).

Conclusion

We found a low incidence of ARF and hyperkalemia in elderly patients treated with ACEIs or ARBs after AMI hospitalization. However, a high rate of treatment discontinuation might prevent a higher rate of occurrence of these events. Long‐term careful monitoring of severe adverse events and timely discontinuation of ACEIs or ARBs among elderly patients with advancing age and CKD after an AMI is warranted in clinical practice.     

A Phase II,open-label,randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens

Objectives To assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) in patients with metastatic colorectal cancer who had failed one or two previous chemotherapeutic regimens that included oxaliplatin and/or irinotecan. Methods This was a Phase II, multicentre, open-label, randomised, two-arm, parallel-group study comparing AZD6244 with capecitabine monotherapy. Patients received either 100 mg twice daily oral AZD6244 free-base suspension every day or 1,250 mg/m² twice daily oral capecitabine, for 2 weeks, followed by a 1-week rest period, in 3-weekly cycles. The primary endpoint was the number of patients experiencing disease progression events. Results Sixty-nine patients were randomised in the study (34 and 35 patients in the AZD6244 and capecitabine groups, respectively). Disease progression events were experienced by 28 patients (∼80%) in both the AZD6244 and capecitabine treatment groups. Median progression-free survival was 81 days and 88 days in the AZD6244 and capecitabine groups, respectively. Ten patients in the AZD6244 treatment arm had a best response of stable disease. For capecitabine, best response was a partial response in one patient, with stable disease in a further 15 patients. The most frequently observed adverse events reported with AZD6244 were acneiform dermatitis, diarrhoea, asthenia and peripheral oedema, compared with hand-foot syndrome, diarrhoea, nausea and abdominal pain with capecitabine. Conclusions AZD6244 showed similar efficacy to capecitabine in terms of the number of patients with a disease progression event and of progression-free survival. AZD6244 is currently undergoing evaluation in Phase II trials in combination with other chemotherapeutic agents.