VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group.

PURPOSE: The aim of this multicenter randomized study was to compare conventional therapy with conventional plus high-dose therapy (HDT) and autologous bone marrow transplantation (ABMT) as front-line treatment for poor-prognosis non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Between October 1991 and June 1995, 124 patients, aged 15 to 60 years, with diffuse intermediate- to high-grade NHL (Working Formulation criteria), stages II bulky (> or = 10 cm), III, or IV were enrolled. Sixty-one patients were randomized to receive etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) for 12 weeks and cisplatin, cytarabine, and dexamethasone (DHAP) as a salvage regimen (arm A), and 63 to receive VACOP-B for 12 weeks plus HDT and ABMT (Arm B). RESULTS: There was no significant difference in terms of complete remissions (CRS) in the two groups: 75% in arm A, and 73% in arm B. The median follow-up observation time was 42 months. The 6-year survival probability was 65% in both arms. There was no difference in disease-free survival (DFS) or progression-free survival (PFS) between the two groups. DFS was 60% and 80% (P = .1) and PFS was 48% and 60% (P = .4) for arms A and B, respectively. Procedure feasibility was the major problem. In arm B, 29% of enrolled patients did not undergo HDT and ABMT. A statistical improvement in terms of DFS (P = .008) and a favorable trend in terms of PFS (P = .08) for intermediate-/high- plus high-risk group patients assigned to HDT and ABMT was observed. CONCLUSION: In this study, conventional chemotherapy followed by HDT and ABMT as front-line therapy seems no more successful than conventional treatment in terms of overall results. However, our results suggest that controlled studies of HDT plus ABMT should be proposed for higher risk patients.

Cemp, a mitoxantrone containing combination, in the treatment of intermediate and high grade non-hodgkin's lymphoma: an effective and non toxic therapeutic alternative for adult and elderly patients.

Here we report the results of a randomised multicenter phase III clinical trial which assesses the therapeutic efficacy and tolerability of a chemotherapy protocol CEMP (cyclophosphamide, etoposide, mitoxantrone and prednisone) in adult and elderly patients with advanced intermediate and high-grade NHL. Between October 1991 and October 1995, 139 patients, aged 55 to 79 years, with diffuse intermediate and high-grade lymphoma, were enrolled. A considerable percentage of patients had clinically aggressive disease: 32.4% had systemic symptoms, 79% had stage III or IV disease, 33.8% had bone marrow involvement, 46% had splenic involvement and 42.5% had increased values of serum lactate dehydrogenate. Complete remission was achieved in 70 of the 139 patients (51.9%) and PR in 12 (16.6%) with an overall response of 68.5%. The overall response survival rate at 6 years was 39%, whereas DFS rate was 48.7% and PFS rate was 28.5%. At four years 49% of the patients were still in CR. Dividing the patients in two groups, under and over 65 years of age, we obtained the same results as far as overall response is concerned. No toxic deaths occurred, neither cardiac, renal nor liver complications happened. CEMP regimen is an effective and safe protocol with good results in elderly people, well comparable to those achieved in younger ones.

Nitrate tolerance in patients with effort angina.

BACKGROUND: In some patients with chronic stable angina the beneficial effects of nitrates may result not only from a reduction in venous return, but also from their action on coronary circulation. In these patients, rate-pressure product at ischemia (RPPI) increases to > 2500 bpm x mmHg after sublingual nitrates (SLN). The relative susceptibility of the venous system and the coronary circulation to the development of nitrate tolerance and the effects of two different drug schedules on the development of tolerance were investigated in patients with these characteristics. METHODS: Five patients were treated with isosorbide-5-mononitrate (IS5MN) 20 bid (8.00 am and 3.00 pm) for 1 week (Group 1) and 5 patients with IS5MN 40 bid (8.00 am and 8.00 pm) for 1 week (Group 2). Tolerance was identified as the decreased effect of SLN; the effects of nitrates were evaluated in relation to: reduction in left ventricle area (delta LVA), which had been measured using equilibrium radionuclide ventriculograms in LAO 45 degrees; this area was considered as an index of the venous return effects; increase in RPPI (delta RPPI), which had been assessed by ergometric test; RPPI was considered an index of coronary flow reserve. Measurements of LVA and RPPI were made in wash-out at the start of the study (delta LVA 1 and delta RPPI 1) and after 1 week of treatment (delta LVA 2 and delta RPPI 2). The mean values of the differences were then evaluated and compared using Student's "t" test. RESULTS AND CONCLUSIONS: In Group 1 patients delta LVA 2 and delta RPPI 2 showed values which were similar to delta LVA 1 and delta RPPI 1 (mean value delta LVA 2 47 vs mean delta LVA 1 48.2 pixels, p = ns; mean value delta RPPI 2 5264 vs mean delta RPPI 1 5536 bpm x mmHg, p = ns). These results suggest that Group 1 patients did not develop tolerance either at the coronary or at the venous level. In Group 2 patients, delta LVA 2 was significantly lower than delta LVA 1 (mean delta LVA 2 18.4 vs mean delta LVA 1 54 pixels, p < 0.01). This finding indicated tolerance to nitrates at the venous level. On the other hand, in all Group 2 patients, values of delta RPPI 2, though lower than delta RPPI 1 (mean delta RPPI 2 3095 vs mean delta RPPI 1 6083 bpm x mmHg, p < 0.01) were still higher than 2500 bpm x mmHg, indicating that the effect of nitrates at the coronary level was preserved. These data suggest that in patients treated with high doses of nitrates, the effect of these drugs at the coronary level is still present when tolerance has already developed at the venous level.

[Diltiazem in spontaneous angina: double-blind cross-over study with Holter monitoring]. / Il diltiazem nell'angina spontanea: studio doppio cieco, cross-over, sotto controllo Holter.

Using Holter monitoring the Authors compared the effectiveness of diltiazem 120 mg every 8 hours for three consecutive days with the results of a placebo administered with the same regimen, following a double-blind completely balanced cross-over trial in 20 patients with angina at rest. During treatment with diltiazem the total number of recorded ischemic episodes was 100, during treatment with placebo the total number was 357 (Tab. I); P less than 0.01 at analysis of variance (Tab. II). Ischemic episodes during treatment with diltiazem had a shorter duration (3.9 versus 5.1 min.), less marked ST segment shifts (1.3 versus 2 mm), and were less symptomatic (20% versus 29%) than ischemic episodes during placebo (Tab. III). No significant differences at a paired t test were noted. Diltiazem was more effective in the morning (12 p.m. - 12 a.m.: from 187 to 34 ischemic episodes) than in the evening (12 a.m. - 12 p.m.: from 170 to 66 ischemic episodes) (Fig. 1); P less than 0.01 at the chi-square test (Tab. IV). Diltiazem reduced the number of ischemic episodes with ST segment elevation, peaking of T waves and negative T wave inversion (from 188 to 39) more than the number of episodes with ST segment depression (from 169 to 61) (Tab. V); P less than 0.05 at the chi-square test. In conclusion, in patients with angina at rest, diltiazem reduces the incidence and seems to reduce the severity of ischemic episodes, too.(ABSTRACT TRUNCATED AT 250 WORDS)

[Evaluation of a new percutaneous nitroglycerin preparation in effort angina]. / Valutazione di un nuovo preparato di nitroglicerina percutanea nell'angina da sforzo.

In 10 subjects with constant threshold effort angina ascertained by two bicycle exercise tests, the efficacy of a new transdermal preparation of nitroglycerin (104 mg) applied once daily was evaluated and compared to that of oral long-acting isosorbide dinitrate (20 mg every 8 hours). The two drugs were administered according to a complete crossover plan. The effectiveness of each drug was evaluated by testing the patients before treatment, on the third and on the twenty-first hour of treatment. In each case the exercise was continued until electrocardiographic signs of ischemia appeared. The total work during treatment with transdermal nitroglycerin was significantly higher (average increase greater than 44%) than without the drug (1311 +/- 545 Kgm before treatment, 2145 +/- 968 Kgm at the third hour, 1899 +/- 657 Kgm at the twenty-first hour of treatment). Similar results were obtained during treatment with isosorbide dinitrate (1332 +/- 581 Kgm before treatment, 1837 +/- 526 at the third hour, 1869 +/- 570 at the twenty-first hour of treatment; average work increase greater than 37%). In conclusion, with this new transdermal preparation of nitroglycerin an increased work-load can be achieved before ischemia appears. Its beneficial action remains constant for 21 hours.

[Myocardial ischemia induced by exercise. Analysis of the recovery phase. Behavior of the rate-pressure normalization product in patients with fixed ischemic threshold and patients with variable ischemic threshold]. / Studio dell'ischemia miocardia indotta dallo sforzo. Analisi della fase di recupero. Comportamento del doppio prodotto di normalizzazione nei pazienti con soglia ischemica variabile e nei pazienti con soglia ischemica fissa.

Traditionally, in patients with exercise-induced myocardial ischemia we analyze the stress-test by studying the behaviour of double product at ischemia. We recognize the presence of a functional component in the reduction of coronary-flow reserve if the double product at ischemia (DPI) varies in 3 stress-tests i.e. more than 20% or more than 3200 mmHg b m'-1. Any analysis that relies exclusively on double product at ischemia is, of necessity, limited to the beginning of the ischemic phenomenon. To better understand the development of the whole event, we also considered the double product calculated when the ischemic electrocardiographic signal regressed (double product of normalization: DPN). More specifically, we set out to determine whether or not double product at ischemia behaviour in patients with variable ischemic threshold (i.e. double product at ischemia variation greater than 3200 mmHg b m'-1) differs from that of patients with fixed ischemic threshold (i.e. double product at ischemia variation less than b m'-1). We performed four multistage bicycle ergometer tests, without drugs, on 19 patients with chronic exertional anginal and exercise-induced ST depression. Patients were tested at the same time of day, within a 10 day period. In the second, third and fourth stress test double product at ischemia was calculated. On the basis of double product at ischemia values in three stress-tests, we distinguished two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute antiarrhythmia treatment with amiodarone and blood levels of thyroid hormones]. / Trattamento antiaritmico acuto con amiodarone e livelli ematici degli ormoni tiroidei.

Amiodarone has a good antiarrhythmic effect administered either acutely or chronically. Since the antiarrhythmic effect of chronically administered amiodarone has been thought to be dependent on a depression of thyroid function, we studied the peripheral hormonal pattern of 10 euthyroid patients with ventricular arrhythmias who had been responsive to the acute intravenous administration of the drug (10 mg/Kg). During the first 12 hours following the drug administration, reverse T3, free T3 and free T4 values and QTc duration were unchanged. Therefore the antiarrhythmic effect of amiodarone when acutely administered has no correlation with thyroid hormone serum changes.

[Chronobiological study of ischemic attacks in angina pectoris at rest]. / Studio cronobiologico degli attacchi ischemici nell'angina a riposo.

The aims of this study were to determine if the hourly distribution of ischaemic episodes differed as regards ST segment elevation or ST segment depression during ischaemic attacks and differed as regards the degree of coronary atherosclerotic involvement. Twenty-four in-patient drug free subjects with angina at rest underwent ECG continuous Holter monitoring for periods varying from 24 to 168 hours. Four groups of patients were identified: group 1A: 6 patients with ST elevation and 0-1 vessel disease; group 1B: 6 patients with ST elevation and 2-3 vessel disease; group 2A: 3 patients with ST depression and 0-1 vessel disease; group 2B: 9 patients with ST depression and 2-3 vessel disease. During Holter monitoring, 301 ischaemic episodes were registered in group 1A during 576 hours; 173 episodes were registered in group 1B during 624 hours; 41 episodes were registered in group 2B during 528 hours. Using the single and population mean cosinor tests on the episodes of each group, considered as a whole, the following results were found: group 1A showed a circadian rhythm with acrophase at 4:03 a.m. (Fig. 2), group 1B showed a circadian rhythm with acrophase at 10:51 a.m. (Fig. 3), group 2A showed a circadian rhythm with acrophase at 11:15 p.m. (Fig. 5), while group 2B showed ultradian rhythms which lasted 7 and 13 hours (Fig. 6). The chronobiologic analysis of the distribution of the ischaemic attacks confirmed the existence of a circadian rhythm of ischaemic episodes in patients with ST elevation.(ABSTRACT TRUNCATED AT 250 WORDS)

VACOP-B, high-dose cyclophosphamide and high-dose therapy with peripheral blood progenitor cell rescue for aggressive non-Hodgkin's lymphoma with bone marrow involvement: a study by the non-Hodgkin's Lymphoma Co-operative Study Group.

BACKGROUND AND OBJECTIVE: Sequential treatment with the addition of high-dose therapy (HDT) and peripheral blood progenitor cell (PBPC) rescue has been reported to be active as front-line therapy in aggressive non-Hodgkin's lymphoma (NHL) with bone marrow (BM) involvement. We designed an intensive sequential therapy as front-line therapy in this subset of patients and conducted a phase II study. DESIGN AND METHODS: Patients with aggressive non-Hodgkin's lymphoma and BM involvement at diagnosis received 8 weeks of VACOP-B chemotherapy as induction therapy. The second phase included high-dose cyclophosphamide (HDCY) (7 g/m(2)) with granulocyte colony-stimulating factor (G-CSF) followed by leukaphereses. The third phase included HDT according to the BEAM protocol or melphalan (140 mg/m(2)) plus total body irradiation (8 Gy in a single dose). RESULTS: Forty patients were included in the study. According to the intention-to-treat, after VACOP-B, 11 (27.5%) and 22 (55%) patients achieved complete remission (CR) and partial remission (PR), respectively. Thirty-four received HDCY. After HDCY, 18 patients (45%) were in CR and 13 (32.5%) in PR. Twenty-nine underwent HDT plus peripheral blood cell rescue (PBPC) rescue. At the completion of treatment 29 patients (72.5%) were in CR, and 3 patients (7.5%) in PR. The actuarial 3-year overall survival, disease free survival and failure free survival are 48%, 55% and 40%, respectively. Overall severe toxicity was 7.5%. INTERPRETATION AND CONCLUSIONS: This phase II study suggests that the intensified treatment described is feasible and active in aggressive NHL with BM involvement. A randomized trial is now underway to test this approach.