Doxorubicin (Adriamycin) was administered by continuous infusion to reduce peak plasma levels and thus lessen cardiac toxicity. Cardiotoxicity was monitored by noninvasive methods, and endomyocardial biopsy specimens were studied by electronmicroscopy. Cardiotoxicity was compared in 21 patients receiving doxorubicin intravenously over 48 or 96 hours and in 30 control patients treated by standard intravenous injection. Both groups were studied prospectively and were well matched by risk factors for doxorubicin cardiotoxicity. The median cumulative dose for those receiving continuous infusion was 600 mg/m2 body surface area (range, 360 to 1500 mg/m2) compared with 465 mg/m2 (range 290 to 680 mg/m2) in the control group (p = 0.002). Fourteen of the 30 patients in the control group showed severe morphologic changes in the biopsy specimens, precluding further doxorubicin administration, as compared with two of 21 patients receiving the drug by continuous infusion (p less than 0.02). The mean pathologic score for the infusion group, 0.9, was lower than the mean for the control group, 1.6 (p = 0.004). Antitumor activity was not compromised. Decreasing peak plasma levels of doxorubicin by continuous infusion reduces cardiotoxicity.

Summary Background Evidence from Europe, Asia, and North America suggests that standard three-drug regimens of a proton pump inhibitor plus amoxicillin and clarithromycin are significantly less effective for eradicating Helicobacter pylori (H. pylori) infection than five-day concomitant and ten-day sequential four-drug regimens that include a nitroimidazole. These four-drug regimens also entail fewer antibiotic doses and thus may be suitable for eradication programs in low-resource settings. Studies are limited from Latin America, however, where the burden of H. pylori-associated diseases is high. Methods We randomised 1463 men and women ages 21–65 selected from general populations in Chile, Colombia, Costa Rica, Honduras, Nicaragua, and Mexico (two sites) who tested positive for H. pylori by a urea breath test (UBT) to: 14 days of lansoprazole, amoxicillin, and clarithromycin (standard therapy); five days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy); or five days of lansoprazole and amoxicillin followed by five of lansoprazole, clarithromycin, and metronidazole (sequential therapy). Eradication was assessed by UBT six–eight weeks after randomisation. Findings In intention-to-treat analyses, the probability of eradication with standard therapy was 82·2%, which was 8·6% higher (95% adjusted CI: 2·6%, 14·5%) than with concomitant therapy (73·6%) and 5·6% higher (95% adjusted CI: −0·04%, 11·6%) than with sequential therapy (76·5%). In analyses limited to the 1314 participants who adhered to their assigned therapy, the probabilities of eradication were 87·1%, 78·7%, and 81·1% with standard, concomitant, and sequential therapies, respectively. Neither four-drug regimen was significantly better than standard triple therapy in any of the seven sites. Interpretation Standard 14-day triple-drug therapy is preferable to five-day concomitant or ten-day sequential four-drug regimens as empiric therapy for H. pylori among diverse Latin American populations. Funding Bill & Melinda Gates Foundation and US National Institutes of Health.

We have studied the clinical impact of elective brain irradiation (EBI) in patients with locally advanced, non-small cell lung cancer (LA-NSC). All patients received combination chemotherapy (cyclophosphamide + doxorubicin (Adriamycin) + cisplatin = CAP) or CAP plus radiotherapy as the initial treatment for their active tumor or as an adjuvant therapy. Of 97 evaluable patients, 46 were randomized to receive EBI (3 000 rad in 10 fractions given over two weeks). The characteristics of both groups were comparable by sex, age, performance status, pretherapy weight loss, histologic cell type, clinical staging, and type of prior therapy. EBI significantly decreased the incidence of central nervous system (CNS) metastasis in the treated group compared to the control group (4% vs 27%, p = .002). CNS involvement occurred in the treated group after failure at other sites whereas 12 of 14 control patients had CNS metastases as the first site of relapse. EBI decreased the incidence of CNS metastasis in all prognostic categories. Using multivariate analysis, the beneficial effect was shown to be significant in females, patients with good performance status, weight loss less than 6%, squamous cell histology, state III disease or no prior therapy. EBI significantly increased CNS metastasis-free interval with a beneficial effect that was significant in males, patients with weight loss less than 6%, squamous cell histology or responders. Although no survival benefit was observed for the treated group because of the adverse effect from other relapses, EBI will become more important as better treatment programs are developed.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of conatumumab, an investigational, fully human monoclonal agonist antibody against human death receptor 5, in patients with advanced solid tumors.Experimental Design: In the dose-escalation phase, patients received escalating intravenous doses of conatumumab (0.3, 1, 3, 10, or 20 mg/kg, 3-9 per cohort) every 2 weeks. In the dose-expansion phase, 10 patients with colorectal cancer (CRC) and 7 with non-small cell lung cancer (NSCLC) received 20 mg/ kg of conatumumab every 2 weeks.Results: Thirty-seven patients received 1 or more doses of conatumumab. Conatumumab seemed to be well tolerated; there were no dose-limiting toxicities. Of adverse events possibly related to treatment, only 3 patients (8%) had a grade 3 event (fatigue and/or elevated lipase), and no anticonatumumab antibodies were detected. An MTD was not reached. Conatumumab exhibited dose linear kinetics from 3 to 20 mg/kg, with a mean terminal half-life of 13 to 19 days. One patient with NSCLC (0.3 mg/kg) had a confirmed partial response (PR) at week 32 (38% reduction in tumor size), with further reduction (48%) by week 96; this patient remains on conatumumab after 4.2 years with a sustained PR. Fourteen patients had a best response of stable disease, 2 for 32 weeks or more. One patient with CRC (0.3 mg/kg) and stable disease for 24 weeks had a 24% reduction in tumor size by RECIST (Response Evaluation Criteria in Solid Tumors) and a 35% reduction in the sum of standardized uptake values of all lesions measured by [18F]fluorodeoxyglucose positron emission tomographic scan. Changes in tumor levels of activated caspase-3 did not appear to be associated with tumor response.Conclusions: Conatumumab can be administered safely up to the target dose of 20 mg/kg every 2 weeks. Clin Cancer Res; 16(23); 5883-91. Ó2010 AACR.