Pathology underrates colon cancer extranodal and nodal metastases; ex vivo radioimmunodetection helps staging.

PURPOSE: Colorectal carcinoma is frequently accompanied by small lymph nodes metastases that often escape pathologic examination. We evaluated whether ex vivo radioimmunodetection with the Affinity Enhancement System (AES) could improve detection of mesocolonic metastases. EXPERIMENTAL DESIGN: A bivalent 111In-labeled hapten was injected (16 patients) 4 days after a bispecific antibody (anticarcinoembryonic antigen, antihapten). Surgery was done 1 to 3 days later, and radioactive uptake in the mesocolon was recorded. Extensive pathologic examination of the mesocolon (reference method) was done after fat dissolution. This method visualizes all lymph nodes but is not in routine use. RESULTS: The reference method disclosed 705 nodes. There was no significant difference between the number of node metastases detected by AES or by the reference method (16 versus 17). Better detection would have been obtained by AES than by routine pathology (P<0.01). In addition 12 extranodal metastases were found in this study of which eight were detected by AES. The prognostic importance of such extranodal metastases has been underlined in the literature. Routine pathology combined with AES would have disclosed all node metastases and 86% of total metastases versus 35% by routine pathology alone. CONCLUSIONS: Ex vivo radioimmunodetection could improve nodal and extranodal metastases detection in patients with colorectal cancer. Its value for improving pathologic analysis, together with the effect of these small metastases on prognosis, should be further evaluated. The benefit of adjuvant chemotherapy for patients upstaged with radioimmunodection should also be assessed because adjuvant chemotherapy improves the 5-year survival of stage III patients.

Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: results of a sequential nonrandomized phase II study. Subcutaneous Administration Propeukin Program Cooperative Group.

PURPOSE: We report the results of the Subcutaneous Administration Propeukin Program (SCAPP) II trial of an outpatient treatment in renal cell carcinoma using interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) administered subcutaneously in combination with fluorouracil (5-FU). The objective of this multicenter trial was to confirm that the combination of IL-2, IFN-alpha, and 5-FU leads to a response rate greater than 20%. PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma were included in this study. During the induction phase of the treatment, which lasted 10 weeks, IL-2 and IFN-alpha were administered subcutaneously three times a week for 8 weeks at doses of 18 MIU and 9 MIU, respectively. During these 8 weeks, every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. After evaluation, responding patients or patients with stable disease (SD) were given maintenance treatment, until disease progression (PD) or the appearance of unacceptable toxicity. Each maintenance cycle consisted of a 2-week treatment followed by a three-week rest period. During treatment, IL-2 and IFN-alpha were administered subcutaneously three times a week at doses of 18 MIU and 9 MIU, respectively. Every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. RESULTS: This trial was closed when the sixth sequential analysis showed the lack of benefit from this combination. At the end of the induction period, of 62 patients, 12 (19%; 95% confidence interval [CI], 10% to 31%) reached an objective response, including one complete response (CR), 16 presented with SD, and 27 showed PD. Twenty-seven patients (43%) developed severe toxicity that required reduction of the planned doses (13 patients), delayed treatment (eight patients), or treatment termination (six patients). Seventeen patients were given maintenance treatment. One- and 2-year survival rates were estimated at 55% and 33%, respectively. The 2-year survival rate was 15% in 11 patients who presented with three poor-prognosis factors and 41% in 51 patients who initially presented with no, one, or two poor-prognosis factors (P = .04). CONCLUSION: As in other recently published studies that used 5-FU, IL-2, and IFN-alpha, the multicenter SCAPP II trial in patients with metastatic renal cell carcinoma generated severe toxicity. This sequential trial failed to confirm the favorable results previously obtained by Atzpodien and Sella with this combination of three drugs. Its efficacy, assessed on the response and survival rates, is near to the results observed in programs that used IL-2 alone given subcutaneously.

Determinants of spontaneous occurrence of sustained monomorphic ventricular tachycardia in right ventricular dysplasia.

OBJECTIVES: We sought to demonstrate the determinants of spontaneous onset of ventricular tachycardia in right ventricular dysplasia. BACKGROUND: Sudden death during athletic activities has been described in patients with right ventricular dysplasia, but few data are available on the clinical circumstances of well tolerated ventricular tachycardias. METHODS: The spontaneous occurrence of 43 episodes of sustained monomorphic ventricular tachycardia was recorded during ambulatory electrocardiographic (Holter) monitoring in 12 patients. RESULTS: The ventricular tachycardia usually occurred without a significant immediate precipitating arrhythmic event: Atrial arrhythmia was never present, and long-short cycle sequences by postextrasystolic pauses or runs of polymorphic extrasystoles were also unusual (four episodes of ventricular tachycardia each). Finally, no arrhythmia was present immediately before the tachycardia in 36 (84%) of the 43 episodes and in 8 of 12 patients. Examination of the sinus rate before the initial episode of tachycardia in each patient showed a continuous increase from 30 min to the few cycles before the tachycardia (mean RR decrease from 876 +/- 778 to 830.5 +/- 189 ms, with a mean slope of approximately 8.4 ms/min; both p = 0.01 by Wilcoxon test). A within-patient comparison showed that the first cycle of the ventricular tachycardia was shorter than that of runs or couplets (389 +/- 88 vs. 453 +/- 121 and 520 +/- 133 ms, p = 0.03 and p < 0.01, respectively, by paired t test) and that the second cycle was shorter than that of runs (383 +/- 96 vs. 435 +/- 120 ms, p = 0.03). Sinus rate measured 15 beats before the event was higher for ventricular tachycardia than for isolated beats (mean RR interval 835 +/- 184 vs. 908 +/- 153 ms, p < 0.01). CONCLUSIONS: Increased heart rate and shortening of the coupling intervals of the first cycles before the tachycardia are due to a change in the vagosympathetic balance with an increased sympathetic tone. This increase appears to be the main determinant of the ventricular tachycardia in this disease in contrast to the multifactorial origin of ventricular tachycardia due to coronary heart disease. It should be considered in patients participating in strenuous athletic activities.

Treatment of newly diagnosed acute promyelocytic leukemia (APL) by a combination of all-trans retinoic acid (ATRA) and chemotherapy. French APL Group.

All-trans retinoic acid (ATRA) is very effective in newly diagnosed acute promyelocytic leukemia (APL), yielding remission (CR) rates of 80 to 90%. However, it is associated with a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome. Furthermore, most patients relapse with maintenance therapy using ATRA alone or low-dose chemotherapy. The French APL group thus designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in the case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. The French group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy), and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low-dose chemotherapy, or both.

Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic myelogenous leukemia patients in chronic phase.

Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.

White blood cell count: a prognostic factor and possible subset indicator of optimal treatment with low-dose adjuvant interferon in primary melanoma.

AlphaIFN has recently been recognized as an adjuvant therapy to surgery in melanoma patients. A major issue is to select patients who will benefit from this therapy and to avoid toxicity in those who will not respond. The aim of this exploratory analysis was to identify the predictive factors of response to alphaIFN. The French cooperative group has recently shown that adjuvant therapy of melanoma patients with low-dose alphaIFN provides a benefit on disease-free interval (DFI). Using this database, predictors of DFI were investigated using Cox models and treatment-covariate interactions were sought. Gender, age, Breslow thickness, and baseline WBC count, given an alphaIFN-WBC interaction, were independent predictors of DFI. Baseline WBC count was the only variable for which there was an interaction with alphaIFN, whatever the Breslow: patients with low WBC count (<6.8 x 10(9)/liter = median) did not benefit from alphaIFN (HR=1.27 (95%CI: 0.84-1.91); P = 0.26) whereas the DFI of patients with high WBC was prolonged (P = 0.0001) with a hazard ratio of 0.50 (95% confidence interval, 0.35-0.71). The estimated values of WBC count for which IFN was significantly superior to no-treatment were those > or = 7.2 x 10(9)/liter. The baseline WBC count was correlated to baseline neutrophils but not to Breslow thickness or to time since last melanoma surgery. AlphaIFN prolonged DFI in patients with a high WBC count but not in those with a low WBC count. The results of this exploratory analysis, if confirmed by other studies, may help to identify patients who are most likely to benefit from alphaIFN.

Superior vena cava syndrome in small-cell lung cancer.

BACKGROUND: The aim of this study was to analyze the features of the superior vena cava syndrome (SVCS) as initial characteristics in small-cell lung cancer: incidence, dissemination of disease, diagnostic procedures, efficacy and toxic effects of chemotherapy, and median survival in patients with SVCS. METHODS: In a prospective series of 724 patients with biopsy-proved small-cell lung cancer seen during a 6-year period, we reviewed data from patients who also had SVCS. RESULTS: The incidence of SVCS was 87 of 724 at the time of diagnosis. Initial emergency radiation therapy was not used in these patients. Diagnostic procedures in these patients were not associated with mortality. Rapid initiation of intensive chemotherapy, often with heparin therapy, resulted in complete or partial responses in 81% and no response in 12%; data were not evaluable in 7%. Two of these 87 patients died of aplasia within 4 weeks of chemotherapy. Median survival was not significantly different in the patients with SVCS (median, 42 weeks) and without SVCS (median, 40 weeks). A significant increase in initial brain metastases at the time of diagnosis was observed in patients with SVCS (22% vs 11%). CONCLUSIONS: Intensive chemotherapy is the first line of therapy in small-cell lung cancer. Histologic diagnostic procedures must be performed in patients with SVCS to adapt the treatment to the underlying cause. Initial emergency radiotherapy, before diagnosis or chemotherapy, does not seem to be useful in these patients. Computed tomography of the brain should be performed routinely in patients with SVCS, and prophylactic brain irradiation could be helpful in such patients. Apparently SVCS is not a poor prognostic factor in treated small-cell lung cancer.

Treatment of early AIDS-related Kaposi's sarcoma with oral all-trans-retinoic acid: results of a sequential non-randomized phase II trial. Kaposi's Sarcoma ANRS Study Group. Agence Nationale de Recherches sur le SIDA.

OBJECTIVE: To assess the efficacy and safety of all-trans-retinoic acid (ATRA), a retinoid with antitumour activity that inhibits in vitro the growth of Kaposi's sarcoma cells, in patients with low-risk AIDS-associated Kaposi's sarcoma. DESIGN: Non-randomized phase II study, using a group sequential procedure to determine whether the response rate to ATRA was above 10%. SETTING: Nine referral French centres. PATIENTS: Twenty HIV-seropositive men with CD4 cells > or = 200 x 10(6)/l, low-risk Kaposi's sarcoma [T0I0S0 according to the classification of AIDS Clinical Trials Group (ACTG)] not previously treated with systemic anti-Kaposi's sarcoma agents, and with at least four measurable lesions were included. INTERVENTIONS: ATRA was given orally 45 mg/m2 daily for 12 weeks. MAIN OUTCOME MEASURE: Tumour response evaluated according to ACTG criteria. RESULTS: Nineteen patients were evaluated for response: partial response, stabilization and progression were found in eight (42%), seven (37%), and four (21%) patients, respectively. Gradual flattening and lightening of lesions was observed in responders after at least 2 months of ATRA. All patients with partial response at week 12 pursued ATRA for another 15+/-7 weeks. Further improvement was observed in six patients. Median duration of response was 332 days. Cheilitis, transient headaches and skin dryness were the main toxicities noted. No significant changes in HIV viral burden or serum interleukin-6 pathways were observed. CONCLUSIONS: ATRA is well tolerated and effective enough in Kaposi's sarcoma patients to warrant further evaluation.

Efficacy of 2-month total parenteral nutrition in AIDS patients: a controlled randomized prospective trial. The French Multicenter Total Parenteral Nutrition Cooperative Group Study.

OBJECTIVE: To evaluate the efficacy of total parenteral nutrition in AIDS patients. DESIGN: A prospective, randomized, controlled, multicentre trial. METHODS: Over a period of 2 months, 31 malnourished and severely immunodepressed AIDS patients were assigned to receive either dietary counselling (n = 15) or home total parenteral nutrition (TPN; n = 16) via a central venous access after an educational program. Results were analysed by intent-to-treat basis. RESULTS: Bodyweight change was +8 kg (+13 +/- 3%) in the TPN group and -3 kg (-6 +/- 2%) in the control group (P < 0.0006). Lean body mass increased in the TPN group (+9 +/- 3%) and decreased in the control group (-5 +/- 3%; P < 0.004) while body cell mass increased in the former (+15 +/- 4%) and decreased in the latter (-12 +/- 6%; P < 0.002). Nutritional subjective global assessment, subjective self-reported health feeling and Karnofsky index were also improved by TPN. Infection line sepsis incidence remained low (0.26 per 100 patient-days). However, no difference in survival rate was exhibited between the two groups by the log-rank test. CONCLUSION: We conclude that home TPN is an efficient treatment of malnutrition in severely immunodepressed AIDS patients.

Trial of oral fumagillin for the treatment of intestinal microsporidiosis in patients with HIV infection. ANRS 054 Study Group. Agence Nationale de Recherche sur le SIDA.

OBJECTIVE: Intestinal microsporidiosis caused by Enterocytozoon bieneusi is a cause of chronic diarrhoea in patients with HIV infection for which there is no current therapy. This study was designed to assess the safety and efficacy of oral fumagillin in this infection. DESIGN: A dose-escalation trial. METHODS: Twenty-nine HIV-infected patients with E. bieneusi infection were consecutively enrolled in the trial. Oral doses of fumagillin were given to four groups of patients for 14 days: 10 mg/day (group 1), 20 mg/day (group 2), 40 mg/day (group 3), and 60 mg/day (group 4). Patients were seen at weeks 1, 2, 4 and 6 to assess safety and efficacy. Efficacy was assessed primarily by the clearance of microsporidia from stools and follow-up duodenal biopsies. RESULTS: Thirteen patients complained of abdominal cramps, vomiting or diarrhoea during the study, and three patients had fumagillin withdrawn because of adverse events. Thrombocytopenia, neutropenia and hyperlipasaemia were the most frequent biological adverse events. Twenty-one out of 29 patients transiently cleared microsporidia from their stools during the study. By week 6, however, all patients in groups 1, 2 and 3 had parasitic relapse. Interestingly, eight out of 11 (72%) patients treated with 60 mg/day (group 4) apparently cleared microsporidia from their gastrointestinal tract and gained weight. No parasitic relapse was documented in these eight patients during a mean follow-up of 11.5 months. CONCLUSION: Treatment with fumagillin at 60 mg/day for 14 days has promise as an effective oral treatment for E. bieneusi infections.

Potential efficacy of fumagillin in intestinal microsporidiosis due to Enterocytozoon bieneusi in patients with HIV infection: results of a drug screening study. The French Microsporidiosis Study Group.

OBJECTIVE: Intestinal microsporidiosis due to Enterocytozoon bieneusi is a frequent cause of chronic diarrhoea in patients with HIV infection for which there is no available therapy. This study was designed to search for a drug with activity against this organism. DESIGN: Prospective open-labelled Phase II multicentre study. SETTING: University hospitals. PATIENTS: Sixty HIV-infected men with intestinal E. bieneusi infection. INTERVENTIONS: Ten drug regimens were consecutively tested orally for 3 weeks: albendazole plus metronidazole, sulphadiazine plus pyrimethamine, atovaquone, doxycycline plus nifuroxazide, itraconazole, flubendazole, chloroquine, paromomycin, sparfloxacin and fumagillin. Nine evaluable patients per regimen were required, but each patient could be enrolled up to three times in the study. OUTCOME MEASURE: Efficacy was assessed primarily by the clearance of E. bieneusi from stools and intestinal biopsies. The safety of each regimen was also assessed. RESULTS: Only purified fumagillin was able to clear E. bieneusi from stools as well as intestinal biopsies, whereas all other regimens failed to show antiparasitic efficacy. However, only four patients received fumagillin because of drug-induced thrombocytopenia. The four patients who received fumagillin remained free of E. bieneusi infection after a mean follow-up of 10 months. CONCLUSION: Eradication of E. bieneusi from the intestinal tract of patients with HIV infection and persistent immunosuppression is an achievable goal. Our study allowed the identification of oral fumagillin as a potential treatment for intestinal microsporidiosis due to E. bieneusi.

Use of Cord Blood Cells for Banking and Transplant.

Allogeneic hematopoietic stem cell (HSC) transplantation has been used to treat thousands of patients, both adults and children, who have life-threatening hematological diseases. The principal limitations of allogeneic bone marrow transplantation (BMT) are, for the majority of patients, the lack of suitable HLA-matched donors and the complications of graft-versus-host disease (GVHD) associated with HLA mismatches. The lack of an HLA-identical sibling donor in 70% of the cases has been overcome through the establishment of registries of potential marrow donors. These registries, however, often are restricted in terms of HLA polymorphism and ethnic diversity. Despite a bone marrow donor registry which contains >3.7 million donors worldwide, some patients cannot be transplanted because of the lack of a suitable HLA-identical donor. New approaches have been investigated, including the use of HLA partially mismatched, T cell-depleted, mobilized peripheral blood HSC or umbilical cord HSC.

Clinico-pathological features and survival of lung cancer patients in Paris, France.

We studied the clinico-pathological features of 750 lung cancers identified in Paris, France, during 1988. An internal comparison was performed between adenocarcinomas and other subtypes. Survival of 502 patients was studied. 85% of patients were males; 93% were smokers or ex-smokers. Squamous cell carcinomas, adenocarcinomas, small cell carcinomas and large cell cancers accounted for 51, 22, 15 and 12% of all cases, respectively. Differences were found for the distribution of histological subtyping according to sex (P = 0.001) and smoking status (P = 0.0001) with a greater proportion of adenocarcinomas for women and non-smokers. Median overall survival was less than one year. In multiple regression analysis, small cell lung cancer patients appeared to have a worse prognosis than other histological subtypes. This study describes patients who were treated in community practice and might be more representative of the real clinico-pathological profile of this disease in France.

Diagnostic and prognostic value of Cyfra 21-1 compared with other tumour markers in patients with non-small cell lung cancer: a prospective study of 116 patients.

The diagnostic value of Cyfra 21-1 in non-small lung cancer (NSCLC) has been established, but few studies have focused on its prognostic value. The aim of this study was to compare that of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, CA 125, neuron-specific enolase and squamous cell carcinoma antigen. 116 patients with unresectable (n = 88) or resectable (n = 28) NSCLC were prospectively monitored from diagnosis, for a median of 14.4 months. All patients underwent tumour-marker determinations before treatment, then every 3 months. Their diagnostic value was studied using ROC (receiver operating characteristic) curves, based on control measure in 23 patients with benign lung diseases. The prognostic analysis was based on overall survival as the main endpoint. The diagnostic value of Cyfra 21-1 was confirmed, with a sensitivity of 54% and a specificity of 96% at a cut-off value of 3.3 ng/ml. At diagnosis, in the 88 non-surgical NSCLC, besides the presence of metastases (P = 0.017), Cyfra 21-1 (P = 0.017) and CA 125 (P = 0.03) were related to outcome. Elevated levels of Cyfra 21-1 at any time during the disease course was selected by multivariate analysis as additional predictors of poor survival.

An ongoing randomized study of neoadjuvant chemotherapy in resectable non-small cell lung cancer.

The purpose of this trial is to assess the possible benefit of neoadjuvant chemotherapy before surgery in patients with operable non-small cell lung cancer. Patients with operable stages I (except T 1N0), II, or IIIA disease are eligible for this ongoing trial. Patients are randomized into two arms. Surgery is performed first in group I; patients found to have T3 tumors or N2 lymph nodes are given postoperative radiotherapy. Group 2 patients start with two cycles of chemotherapy; following surgery, two more cycles are administered in responder patients and, as in group I, patients with T3 tumors or N2 lymph nodes are given radiotherapy. Chemotherapy is the MIP protocol: mitomycin 6 mg/m2 day I, ifosfamide 1.5 g/m2 days 1 to 3, cisplatin 30 mg/m2 days I to 3, and mesna 1,200 mg/m2 days 1 to 3. One hundred fifty patients were enrolled between June 1991 and September 1993. By the time this report was prepared, 117 patients had completed all assigned treatment, 63 in group I and 54 in group 2. There were two ineligible patients, one in each group. Forty-nine patients underwent thoracotomy in the chemotherapy-surgery group and 62 in the surgery-only group. There was only one progression after two cycles of chemotherapy. Rates of exploratory and incomplete surgery were 17% in group I and 12% in group 2. The trial is ongoing.

Age as the main prognostic factor in adult aggressive non-Hodgkin's lymphoma.

From 1975 to 1983, 73 patients with aggressive non-Hodgkin's lymphoma were treated with a first-generation program including Adriamycin, VM 26, cyclophosphamide, and prednisone. Thirty-nine patients were under 60 years of age, and 34 were 60 years or older. The clinical and histologic characteristics of the two groups were similar. Using either univariate or multivariate analysis, age appeared as the only prognostic factor. Patients under 60 had a median survival of 48 months, with a five-year survival rate of 47 percent and a five-year disease-free survival rate for complete-remission patients of 72 percent. Patients 60 years or older had a median survival of 18 months with a five-year survival rate of 18 percent and a five-year disease-free survival rate for complete-remission patients of 24 percent. These highly significant differences were related to a non-significantly decreased complete-remission rate and a significantly higher relapse rate in elderly patients. Since patient selection according to age could play a role in the results achieved with intensive chemotherapy programs, randomized trials comparing the various chemotherapy programs for aggressive non-Hodgkin's lymphoma are warranted.

Bone densitometry in patients with multiple myeloma.

PURPOSE, PATIENTS, AND METHODS: We performed dual-energy x-ray absorptiometry in 10 selected patients with aggressive multiple myeloma in whom substantial tumor mass reduction was achieved after high-dose chemoradiotherapy followed by autologous blood stem cell transplantation. RESULTS: In most cases, bone mineral density (BMD) of the spine was initially low (Mean Z score: -2.69, SEM 0.76) and dramatically increased after treatment (mean increase 16.4%; 7.7% with 95% confidence interval 2.2 to 12.2, excluding one patient whose spine BMD increased by 94.8%). In contrast, skeletal roentgenograms, computed tomographic scans, and magnetic resonance imaging did not reveal any significant improvement of patients' bone lesions. CONCLUSIONS: In patients with multiple myeloma, bone densitometry could be a useful way to assess the efficacy of treatment on bone status.

Long-term efficacy of a new, fixed, very-low-dose angiotensin-converting enzyme-inhibitor/diuretic combination as first-line therapy in elderly hypertensive patients.

OBJECTIVE: To determine the long-term efficacy and safety of a fixed, very-low-dose tablet combining one-half the standard dose of perindopril with one-quarter the standard dose of indapamide as first-line treatment in elderly patients. DESIGN: Double-blind, randomized, placebo-controlled study in an outpatient setting. PATIENTS AND INTERVENTIONS: Following a single-blind, placebo run-in period of 4 weeks, patients [65-85 years, with mild-to-moderate essential hypertension or isolated systolic hypertension (ISH)] were randomized to receive one tablet of perindopril 2 mg/indapamide 0.625 mg (Per/ Ind) (n=193) or placebo (n=190), daily for 12 weeks. After this first 12-week period, all patients on Per/Ind (n=138) and patients responding to placebo (n=61) were maintained on their previous regimen for a further 48 weeks. Patients in the placebo group whose blood pressure was not normalized, were switched to Per/Ind (n=60). MAIN OUTCOME MEASURE: The primary endpoint was the proportion of patients with blood pressure that normalized between weeks 0 and 60. RESULTS: After 1 year of treatment (intention-to-treat) supine systolic and diastolic blood pressure decreased by 23.0 +/- 15.3 mmHg and 13.3 +/- 94 mmHg with Per/Ind (n=253: 193 from randomized Per/Ind group and 60 from the placebo group switched at week 12). The mean decreases in systolic blood pressure were similar in essential hypertension and ISH (systolic blood pressure 23.2 versus 22.7 mmHg, respectively). Per/Ind treatment (n=253) achieved an initial normalization of blood pressure in 96.2% [95% confidence interval (CI) 93.6-98.9%; Kaplan-Meier estimate] of Per/Ind-treated patients; 79.8% (95% CI 74.1-85.5%) of these maintained a normalized blood pressure throughout the 1 -year follow-up. The incidence of adverse events was similarly low in the placebo and active therapy groups. Efficacy and safety results for the over 75 years subgroup were similar to those for the younger elderly subjects CONCLUSIONS: The fixed, very low-dose combination of perindopril 2 mg/indapamide 0.625 mg results in sustained blood pressure control when used as first line treatment of elderly hypertensive patients over 1-year, and is well-tolerated.

A comparison of indapamide SR 1.5 mg with both amlodipine 5 mg and hydrochlorothiazide 25 mg in elderly hypertensive patients: a randomized double-blind controlled study.

OBJECTIVE: To analyse the efficacy of indapamide sustained-release (SR) 1.5 mg in reducing blood pressure versus amlodipine 5 mg and hydrochlorothiazide 25 mg, in elderly hypertensive patients. DESIGN: Double-blind, randomized, 12 week study using three parallel groups. SETTING: European teaching hospitals and general practices. PATIENTS: Randomized patients, (n = 524) including 128 patients with isolated systolic hypertension (ISH); mean age: 72.4 years; mean systolic/diastolic blood pressures (SBP/DBP): 174.5/97.9 mmHg. MAIN OUTCOME MEASURES: Clinic systolic and diastolic blood pressure variations. RESULTS: Indapamide SR 1.5 mg demonstrates a similar efficacy to that of amlodipine 5 mg, as well as to that of hydrochlorothiazide 25 mg (equivalence P < 0.001); the mean decreases in SBP/DBP were -22.7/-11.8 mmHg, -22.2/-10.7 mmHg and -19.4/-10.8 mmHg, respectively. In the ISH subgroup, indapamide SR 1.5 mg tends to have greater efficacy than hydrochlorothiazide 25 mg in reducing the SBP (-24.7 versus -18.5 mmHg, respectively; equivalence P = 0.117), while similar results are obtained with amlodipine 5 mg (-23 mmHg, equivalence P < 0.001). The normalization rate was relatively high for indapamide SR 1.5 mg (75.3%), when compared with amlodipine (66.9%) and hydrochlorothiazide (67.3%), especially in the subgroup of isolated systolic hypertensive patients: 84.2 versus 80.0% for amlodipine, and versus 71.4% for hydrochlorothiazide. CONCLUSIONS: Indapamide SR 1.5 mg shows similar antihypertensive efficacy to amlodipine 5 mg and hydrochlorothiazide 25 mg in elderly hypertensive patients, while in patients with isolated systolic hypertension, indapamide SR 1.5 mg shows a similar efficacy to amlodipine 5 mg but a greater efficacy than hydrochlorothiazide 25 mg.

An equivalence study of the safety and efficacy of a fixed-dose combination of perindopril with indapamide versus fixed-dose combinations of captopril with hydrochlorothiazide and enalapril with hydrochlorothiazide in the treatment of hypertension.

OBJECTIVE: The aim of this multicenter, randomly allocated, double-blind, parallel-group study was to evaluate the equivalence of three fixed-dose combination drugs in mild to moderate hypertension: perindopril + indapamide (4 + 1.25 mg), captopril + hydrochlorothiazide (50 + 25 mg) and enalapril + hydrochlorothiazide (20 + 12.5 mg). PATIENTS AND METHODS: After a single-blind, 4-week, placebo run-in phase, 527 patients (mean +/- SD age 54.5 +/- 1.2 years) with a supine diastolic blood pressure of 101.2-101.7 mmHg were randomly assigned to one of the three treatments for 8 weeks. The main evaluation criteria were diastolic blood pressure and serum potassium concentration. Equivalence was assessed on an intention-to-treat basis, using Schuirmann's method, which involves performing two one-tailed statistical tests on the data. Thirty-five patients were withdrawn from the study but there were no differences between groups in the reasons for withdrawal. RESULTS: Diastolic blood pressure decreased by between 13.1 and 14.2 mmHg in the three groups. The 90% confidence intervals for the differences between perindopril + indapamide and the other treatments were -1.1, +1.7 mmHg for captopril + hydrochlorothiazide and -0.4, +2.6 mmHg for enalapril + hydrochlorothiazide. Schuirmann's test was highly statistically significant (P<0.001 for perindopril + indapamide versus captopril + hydrochlorothiazide; P<0.002 for perindopril + indapamide versus enalapril + hydrochlorothiazide), so that the two one-sided hypotheses that the treatments were not equivalent were rejected at the nominal level of alpha = 0.05. Similarly, the safety of the treatments was equivalent in terms of serum potassium. The 90% confidence intervals of the differences between perindopril + indapamide and the other treatments were -8.7, -1.6% for captopril + hydrochlorothiazide (P = 0.004) and -1.5, +2.7% for enalapril + hydrochlorothiazide (P<0.001). CONCLUSIONS: We conclude that the safety and efficacy of perindopril + indapamide, captopril + hydrochlorothiazide and enalapril + hydrochlorothiazide were equivalent after 8 weeks of treatment in patients with mild to moderate hypertension.