Search

Abstract. The aim of this phase II study was to evaluate toxicity, response, time to progression, and overall survival in patients with recurrent or progressive small cell lung cancer (SCLC) [...]

Byline: Georg A. Bjarnason (1), Danielle Charpentier (2), Ralph Wong (3), Rakesh Goel (4), Lynn Douglas (5), Wendy Walsh (6), Sarah Matthews (6), Susan Dent (7), Lesley Seymour (6) Keywords: Doxorubicin; gastric cancer; Tomudex; phase-I study Abstract: Background: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) and recommended phase II dose for Tomudex and doxorubicin when given in combination to patients with advanced metastatic cancer. The secondary objective was to assess the toxicity profile. Patients and methods: Starting doses were Tomudex 2.5 mg/m.sup.2 i.v. bolus day 1 and Doxorubicin 30 mg/m.sup.2 i.v. bolus day 1, repeated every 3 weeks. Doxorubicin was escalated in increments of 10 mg/m.sup.2 to 60 mg/m.sup.2, followed by escalation of Tomudex in increments of 0.5 mg/m.sup.2 to 3.5 mg/m.sup.2, on six dose levels. Twenty-five patients received 127 cycles of therapy, with at least 3 patients treated at each dose level. Results: There was no dose limiting toxicity (DLT) observed in the first five dose levels. Three of six patients on dose level six had DLT. Further dose escalation was not warranted and this was declared the MTD. Grade 3 or 4 granulocytopenia was observed in 16/25 patients, with associated fever in 3/25 patients. Responses were seen in this study with one complete response (duration 12.8 months) and 3 partial responses (median duration 8 months) in 21 evaluable patients. Fourteen patients had stable disease (median duration 2.5 months). All 4 responding patients and 10 patients with stable disease had gastric cancer. Conclusions: The recommended phase-II dose for this combination in future studies is Tomudex 3 mg/m.sup.2 and doxorubicin 60 mg/m.sup.2 given every 3 weeks. Author Affiliation: (1) The Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada (2) CHUM Hopital Notre-Dame, Montreal, Quebec, Canada (3) Cancer Care Manitoba, Winnipeg, Manitoba, Canada (4) Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada (5) AstraZeneca Pharma Canada, Mississauga, Ontario, Canada (6) National Cancer Institute of Canada, Clinical Trials Group, Kingston, Ontario, Canada (7) Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada Article History: Registration Date: 14/11/2004 Article note: An erratum to this article can be found at http://dx.doi.org/10.1007/s10637-005-1447-x.

Byline: Jose Luis Firvida (1), Margarita Amenedo (2), Ruben Rodriguez (1), Ana Gonzalez (2), Mercedes Salgado (1), Manuel Ramos (2), Gustavo Losada (2) Keywords: docetaxel; fractionated cisplatin; non-small cell lung cancer Abstract: This phase II trial evaluated the efficacy and safety of docetaxel 85 mg/m.sup.2 (day 1) and cisplatin 80 mg/m.sup.2 (administered as 40 mg/m.sup.2 doses each on days 1 and 2) every 3 weeks as first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Forty-two NSCLC patients were enrolled, most of them with stage IV disease (74%). A total of 195 chemotherapy cycles were administered (median 6, range 1--6). All patients were considered evaluable for efficacy and toxicity in an intention-to-treat (ITT) analysis. The overall response rate was 48% (95% CI, 33--64), including one CR (3%) and 19 PRs (45%). Stable disease was found in 6 patients (14%). The median time to disease progression was 4.9 months (95% CI, 4.0--5.7) and the median overall survival was 10.5 months (95% CI, 5.1--16.0). The survival rates at 1 and 2 years were 36.0% (95% CI, 19.9--52.0) and 18.0% (95% CI, 3.9--32.1), respectively. Overall, the combination showed an excellent safety profile. Severe hematological toxicities were uncommon: neutropenia (5% of patients, 1% of cycles) and febrile neutropenia (2% of patients, 0.5% of cycles). Asthenia (12%) was the only grade 3/4 non-hematological toxicity that affected more than 10% of patients. There were no toxic deaths. In conclusion, docetaxel plus fractionated cisplatin as first-line treatment of advanced NSCLC patients showed similar efficacy as the same combination with higher doses of docetaxel but where cisplatin was administered in a single dose. This new schedule shows promise in its excellent hematological and non-hematological toxicity profile. A randomized phase III trial is needed to confirm these results. Author Affiliation: (1) Complejo Hospitalario de Ourense, Ourense, Spain (2) Centro Oncologico de Galicia, A Coruna, Spain Article History: Registration Date: 02/10/2004

Byline: Devansu Tewari (1), Bradley J. Monk (1), Mark Hunter (1), Camille A. Falkner (1), Robert A. Burger (1) Keywords: gemcitabine; cisplatin; platinum-resistant ovarian cancer Abstract: The treatment of recurrent ovarian cancer with the combination of gemcitabine and cisplatin chemotherapy has recently been shown to be an active regimen. But the majority of positive responses have been observed in patients considered either platinum-sensitive or who have had extended platinum-free intervals. The purpose of our study was to review our experience with this regimen in women with platinum-resistant ovarian and peritoneal carcinoma with more recent exposure to platinum. We studied twenty-two patients who had relapsed within six months of their most recent platinum-based regimen and were treated with gemcitabine (450--600 mg/m.sup.2) and cisplatin (30 mg/m.sup.2) on days 1 and 8 of a 21-day cycle. The overall response rate was 64% (95% C.I. 42--85%) with seven (32%) complete and seven (32%) partial responses. The median progression-free interval was 6.7 months for responding patients and 3.9 months for the entire study group. Median survival for responders was 15.8 months compared to 8.8 months for non-responders. Overall survival was 11.4 months. Grade 3 or 4 toxicity was encountered in 59% of treatments. We conclude from this limited review that the combination of gemcitabine and cisplatin chemotherapy is an active regimen in platinum-resistant ovarian and peritoneal carcinoma and warrants consideration in the management of patients with recurrent disease. Author Affiliation: (1) Chao Family Comprehensive Cancer Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Irvine-Medical Center, 101 The City Drive, Orange, CA, 92868, USA Article History: Registration Date: 02/10/2004

Byline: Carmen Plasencia (1), Albert Abad (1), Eva Martinez-Balibrea (1), Miquel Taron (1) Keywords: cell culture; synergism; antagonism; platinum agents; 5-Fluorouracil; Irinotecan Abstract: Purpose: ZD0473 (AMD473) [cis-amminedichloro(2-methylpyridine) platinum(II)] is a novel platinum agent of proven activity in vitro against a variety of human tumor-derived cell lines even with intrinsic or acquired resistance to CDDP. The aim of this study is to provide the basis for a rational design of ZD0473-based combination in colon cancer. Experimental design: We evaluated the cytotoxic effect of ZD0473 administered alone or in combination with 5-Fluorouracil (5FU) or SN38 in a panel of sensitive and 5FU-resistant colorectal cell lines (HT29/HT29-5FUR and LoVo/LoVo-5FUR). We analyzed four sequential schedules of administration: ZD0473 [right arrow] 5FU, 5FU [right arrow] ZD0473, ZD0473 [right arrow] SN38 and SN38 [right arrow] ZD0473. MTT-assay and isobologram analyses were performed to determine the synergism/antagonism. Results: The pattern of response towards ZD0473, administered as single agent, was similar in all cases and independent of the 5FU-resistance phenotype (IC50 from 48.1 to 76.6 uM) and/or p53 status. No differences in sensitivity to ZD0473 alone or in combination were observed between DNA-mismatch repair-proficient (HT29/HT29-5FUR) and -deficient (LoVo/LoVo-5FUR) cells. ZD0473 administered prior to 5FU leads to synergistic/additive effect in all cell lines, while the 5FU [right arrow] ZD047 schedule was only synergistic in HT29 cells. Exposure to ZD0473 prior to SN38 leads to a synergistic/additive schedule in LoVo/LoVo-5FUR cells, while SN38 [right arrow] ZD0473 schedule was only synergistic in parental cell lines. Conclusions: The combinations of ZD0473 and 5FU or SN38 have shown to be active in sensitive and 5FU-resistant colorectal cell lines when a correct schedule of administration is applied. These results may be further exploited to promote new schedules of administration for advanced colorectal cancer treatment. Author Affiliation: (1) Medical Oncology Service and Laboratory of Molecular Biology, Hospital Universitari Germans Trias i Pujol, Spain Article History: Registration Date: 02/10/2004

The treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder.

Byline: Paulo M. Hoff (1), Everardo D. Saad (2), Richard Pazdur (3), Robert Wolff (1), Yvonne Lassere (1), Karla R. Bogaard (1), James L. Abbruzzese (1) Keywords: colorectal neoplasms; drug therapy; phase I; irinotecan; oxaliplatin Abstract: Background: Both irinotecan and oxaliplatin are active agents in the treatment of patients with metastatic colorectal cancer (MCC). There is a strong preclinical rationale for combining these two agents. We sought to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of combined irinotecan and oxaliplatin given every three weeks. Methods: Cohorts of patients with MCC previously treated with 5-fluorouracil received escalating doses of irinotecan (150, 175, and 200 mg/m.sup.2) and a fixed dose of oxaliplatin (130 mg/m.sup.2), both given intravenously every 3 weeks. DLT was evaluated within the first course of treatment. Objective responses were evaluated every two courses and were confirmed at least four weeks later. Results: Fourteen patients were treated and evaluated for toxicity. The DLT was neutropenia, with or without fever, and delayed recovery of neutrophil counts was frequent (13 courses in six patients). Other toxic effects (peripheral neuropathy, nausea, vomiting, diarrhea, and fatigue) were mild to moderate. Among 13 patients evaluable for activity, four achieved partial responses and nine had stable disease. Conclusion: The combination of irinotecan and oxaliplatin is safe and apparently active in the treatment of MCC patients. The recommended dose for phase II studies is 175 mg/m.sup.2 irinotecan plus 130 mg/m.sup.2 oxaliplatin, given every 3 weeks. Neutropenia and delayed recovery of neutrophil counts are the predominant early toxicities with this schedule. Author Affiliation: (1) Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX (2) Albert Einstein Hospital, Sao Paulo, Brazil (3) U.S. Food and Drug Administration, Rockville, MD, USA Article History: Registration Date: 21/10/2004

The combination of peginterferon and ribavirin was significantly more effective in achieving a sustained virologic response than was the combination of interferon and ribavirin in subjects who were coinfected with HCV and HIV in a study. The marked discrepancy in the rates of sustained virologic response between HCV genotypes indicates that strategies are needed to improve the outcome in persons infected with HCV genotype 1.

In this large, randomized, placebo controlled trial, peginterferon Alfa-2a plus ribavirin elicited significantly higher rates of sustained virologic response than interferon Alfa-2a plus ribavirin in patients infected with both HIV and HCV. The combination of peginterferon Alfa-2a plus ribavirin was significantly more effective than either interferon Alfa-2a plus ribavirin or peginterferon Alfa-2a monotherapy.

Cetuximab is given alone or in combination with irinotecan to patients with metastatic colorectal cancer. The efficacy of this was tested on 329 randomly assigned patients and ceuximab showed significant clinical activity.

Simultaneous treatment with three antiviral medications appears to be substantially more effective at reducing viral loads than sequential use of the drugs in HIV infection. Researchers treated 97 HIV patients with indinavir, zidovudine, and lamivudine together or sequentially. Seventy-eight percent of patients who received the simultaneous three-drug regimen achieved clinically significant viral load reductions, which persisted at 100 weeks. Only 30-45% of those who took the drugs in sequence achieved the same level of viral suppression.

Byline: Kazumoto Iijima (1), Seiko Ito-Kariya (1), Hajime Nakamura (1), Norishige Yoshikawa (1) Keywords: Key words: Henoch-Schonlein nephritis; Multiple combined therapy; Histological effects; Prognosis Abstract: From 1980 through 1992, 14 children with Henoch-Schonlein nephritis (HSN) showing severe glomerular changes (grade IV or V) were given a multiple combined therapy with prednisolone, cyclophosphamide, heparin/warfarin, and dipyridamole, and were followed for 7.5+-0.9 years. The period between the onset of nephritis and the start of therapy was 0.8+-0.4 years. Ten patients underwent follow-up biopsy after therapy. The percentage of glomeruli having crescents/segmental lesions was significantly reduced after therapy (70%+-5% vs. 42%+-7%, P &lt 0.01), due mainly to the resolution of crescents (51%+-8% vs. 13%+-5%, P &lt 0.01). Thus, histological grade was significantly improved (5 grade IV and 5 grade V vs. 7 grade III and 3 grade IV, P &lt 0.01). After an average follow-up period of 7.5 years, 9 patients showed normal urine and renal function, 4 showed minor urinary abnormalities, and 1 heavy proteinuria. No patient developed chronic renal insufficiency. These findings suggest that the multiple combined therapy could be effective for histologically severe HSN, although a prospective controlled study should be performed. Author Affiliation: (1) Department of Pediatrics and Faculty of Health Science, Kobe University School of Medicine, Kobe, Japan, JP Article note: Received July 2, 1997 received in revised form September 26, 1997 accepted October 2, 1997

Byline: Sita. Jayalakshmi, Ramana. Reddy, Rupam. Borgohain, C. Subramanyam, Manas. Panigrahi, C. Sundaram, A. Meena, S. Mohandas Introduction: Rhinocerebral mycosis is a rapidly progressive fatal opportunistic infection, predominantly affecting people [...]

Currently available antidepressant medications are effective for a large segment of the population with depression. However, recent data suggest that a sizable portion of patients with unipolar depression do not [...]

There is considerable exigency to take all necessary steps to cure tuberculosis cases and prevent further emergence of drug-resistant tuberculosis. The most important of these steps is to ensure that the treatment, particularly of sputum smear-positive cases, is adequate and that patients adhere to their treatment by supervised, direct observation of drug-taking according to the standardized regimens. Use of fixed-dose combinations (FDCs) of tablets against tuberculosis is now being recommended by WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) as an additional step to ensuring proper treatment. FDCs simplify the prescription of drugs and the management of drug supply, and may also limit the risk of drug-resistant tuberculosis arising as a result of inappropriate drug selection and monotherapy. Only FDCs of proven quality and proven rifampicin bioavailability should be purchased and used. In most situations, blood levels of the drugs are inadequate because of poor drug quality rather than poor absorption. This is true irrespective of the human immunodeficiency virus (HIV) infection status of the tuberculosis patients (other than those with overt acquired immunodeficiency syndrome, with CD4 counts [is less than]200 cells/[mm.sup.3]). Currently, WHO, IUATLD and their partners are developing strategies for ensuring that only quality FDCs are used in tuberculosis programmes. A simplified and effective protocol for assessment of rifampicin bioavailability has been developed, and laboratories are being recruited to form a supranational network for quality assurance of FDCs. Standardization of FDC drug formulations has been proposed, which limits rifampicin-containing preparations to nine (including a four-drug FDC and three paediatric FDCs). Keywords: tuberculosis, pulmonary, drug therapy; tuberculosis, multidrug-resistant, drug therapy; drug therapy, combination; drug resistance; antitubercular agents, administration and dosage; antitubercular agents, standards; rifampin, pharmacokinetics. Mots cles: tuberculose pulmonaire, chimiotherapie; tuberculose resistante a la polychimiotherapie, chimiotherapie; polychimiotherapie; resistance aux medicaments; antituberculeux, administration et posologie; antituberculeux, normes; rifampicine, pharmacocinetique. Palabras clave: tuberculosis pulmonar, quimioterapia; tuberculosis resistente a multidrogas, quimioterapia; quimioterapia combinada; resistencia a las drogas; agentes antituberculosos, administracibn y dosificacion; agentes antituberculosos, normas; rifampin, farmacocinetica., Bulletin of the World Health Organization, 2001, 79: 61-68. Voir page 66 le resume en francais. En la pagina 67 figura un resumen en espanol. Introduction Tuberculosis has been a [...]