Cyclophosphamide-methotrexate 'metronomic' chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation.

BACKGROUND: Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks-is a potentially novel approach to the control of advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has, as an advantage, the property of significantly reducing undesirable toxic side-effects. The aim of the present study was to evaluate the cost effectiveness of cyclophosphamide-methotrexate 'metronomic' chemotherapy in the palliative treatment of pretreated metastatic breast cancer. METHODS: Low-dose cyclophosphamide-methotrexate 'metronomic' chemotherapy was compared with outcome and resource utilisation data of published phase II trials regarding metastatic breast cancer, performed in western countries, mostly in Europe. All direct costs associated with metastatic breast cancer treatment were included and adjusted to year 2003 values. Sensitivity analyses were performed and variations to the values of key parameters were assessed. RESULTS: Low-dose cyclophosphamide-methotrexate 'metronomic' therapy was assessed to be a cost-effective/cost-saving therapy for palliative treatment for metastatic breast cancer when compared with novel chemotherapy strategies (phase II trials). Compared with the 11 phase II mono- and combination chemotherapies, metronomic treatment showed marked cost savings in each case and improved cost effectiveness. Sensitivity analyses showed the results were robust to variations to the values of key parameters with very few exceptions. CONCLUSIONS: Metronomic cyclophosphamide-methotrexate is significantly cost effective. If validated by prospective randomized trials, the treatment concept could reduce healthcare costs, especially those associated with the combined use of new, highly expensive, molecularly targeted therapies.

Double-blind, randomized, controlled study on the efficacy and safety of a novel diclofenac epolamine gel formulated with lecithin for the treatment of sprains, strains and contusions.

To evaluate the efficacy of the new diclofenac-N-(2-hydroxyethyl)-pyrrolidine gel formulated with lecithin (DHEP lecithin) compared with diclofenac-N-(2-hydroxyethyl)-pyrrolidine gel (DHEP gel) without lecithin in mild-to-moderate posttraumatic injuries (grade 1 ankle, knee and muscle injuries), a multicenter, double-blind, controlled study was carried out. A total of 100 patients were enrolled and randomly assigned to either DHEP lecithin (n = 52) or DHEP gel (n = 48) treatment. All patients concluded the treatment period except for five, who did not turn up to their respective investigational sites for the follow-up visits. According to an intention-to-treat approach, they were all included in the statistical analysis. As for the efficacy and safety analysis, the primary variable was "pain on movement" as measured by a Huskisson visual analog scale. During the first 3 days of treatment each group recorded a significant within-group decrease, but patients treated with DHEP lecithin showed a decrease in absolute value that was statistically greater than that obtained with DHEP gel (p = 0.025). At the end of the treatment period (day 10) the difference between groups was still statistically significant (p = 0.036). The statistical analysis of the secondary efficacy variables showed significant results in favor of DHEP lecithin treatment. These were superimposable on the results found for the primary variable. The global efficacy and tolerability judgments, reported either by patient or by physician, showed no statistical difference between treatment groups. Due to the presence of lecithin in the new gel formulation, DHEP lecithin showed a faster and significantly more marked therapeutic effect compared with that of DHEP gel.

Double-blind, randomized clinical study comparing hyaluronic acid cream to placebo in patients treated with radiotherapy.

PURPOSE: The effect of hyaluronic acid (Ialugen cream) on acute skin reactions after radiotherapy, was assessed in a randomized, double-blind, placebo-controlled study. MATERIAL AND METHODS: Out of the 152 patients presenting with head and neck, breast or pelvic carcinomas and registered in the study, 134 cases-70 in the Ialugen group (IA) and 64 in the placebo group (PBO)-completed their IA or PBO treatment. At the time of randomisation, these two groups were balanced for sex, age, weight and height. The mean total dose of radiation given during the study was 60.6 +/- 10.9 Gy in the IA group and 64.3 +/- 10.8 Gy in the PBO group (P = 0.47). RESULTS: Acute radio-epithelitis scores were significantly higher in the PBO group than in the IA group, starting from the control at week 3 and throughout the 6 weeks of treatment (P < 0.01 from week 3 to week 7; P < 0.05 at weeks 8 and 10). Likewise, the global efficacy judgement expressed, at the end of treatment, by both the physician and the patient showed a significant difference in favour of Ialugen (P < 0.01 and P < 0.05, respectively). There was no significant difference of tolerance between the IA and PBO treatments (P = 0.18 according to the physician and P = 0.42 from the patient's viewpoint). CONCLUSION: The prophylactic use of a cream with hyaluronic acid is shown to reduce the incidence of high grade radio-epithelitis, suggesting an interesting role of the hyaluronic acid cream as supportive treatment to improve compliance and quality of life in patients undergoing radiation therapy.

Effects of short-term reduction in serum cholesterol with simvastatin in patients with stable angina pectoris and mild to moderate hypercholesterolemia.

To evaluate the effects of short-term cholesterol-lowering treatment on myocardial effort ischemia, 22 patients with stable effort ischemia and mild to moderate hypercholesterolemia (low density lipoprotein [LDL] cholesterol 160 to 220 mg/dl) were randomly allocated at baseline (TO) in 2 groups. Group A included 12 patients treated with simvastatin 10 mg bid; group B included 10 patients treated with placebo. All patients underwent a treadmill electrocardiography (ECG) test; total cholesterol, HDL and LDL cholesterol, triglycerides, plasma, and blood viscosity were measured. All tests were repeated after 4 and 12 weeks. For 18 of the same patients (11 taking simvastatin, 7 receiving placebo), forearm strain-gouge plethysmography was performed at baseline and after 4 weeks, both at rest and during reactive hyperemia. At 4 and 12 weeks, group A showed a significant reduction in total cholesterol (p <0.05) and LDL (p <0.05), with unchanged HDL, triglycerides, blood, and plasma viscosity. Effort was unmodified, ST-segment depression at peak effort and ischemic threshold were significantly improved after 4 and 12 weeks (all p <0.05) with unchanged heart rate x systolic blood pressure product. A significant increase in the excess flow response to reactive hyperemia was detected in group A (p <0.03); group B showed no changes in hematochemical and ergometric parameters. These data suggest that cholesterol-lowering treatment is associated with an improvement in myocardial effort ischemia; this might be explained by a more pronounced increase of coronary blood flow and capacity of vasodilation in response to effort.

Management of the patient with left ventricular hypertrophy.

The management of left ventricular hypertrophy (LVH) presupposes that the patient is identified by echocardiography and is carefully evaluated for risk stratification, taking into consideration possible associated complications. The role of non-pharmacological treatment is limited, except in obese patients. Drug treatment, especially using calcium antagonists, angiotensin converting enzyme inhibitors and beta-blockers, has proved to be effective in reducing LVH. These drugs are also effective in controlling, if not reversing, the associated pathophysiological changes and complications, such as impaired systolic and diastolic function, and ventricular arrhythmias. There is, however, no evidence of any beneficial effect on myocardial ischaemia. The desirable goal is LVH regression, but it may not be achievable in over 50% of patients, and it is not possible to identify patients in whom regression is likely. Regression, or control of each sequelae, could prevent sudden death, the evolution of hypertensive heart disease leading to heart failure and, probably, myocardial infarction. Patients must be followed carefully during and, particularly, at the beginning of the antihypertensive therapy which has to be gradually introduced. At best, blood pressure must be reduced while avoiding hypotension. The strategy of antihypertensive treatment has to be reconsidered on the basis of the presence of LVH and could lead to decreased cardiovascular morbidity and mortality of patients with LVH.

A double-blind comparison of nicorandil and metoprolol in stable effort angina pectoris.

The antianginal activities of nicorandil, 10 and 20 mg bid, and metoprolol, 100 mg bid, were compared in patients with stable effort angina pectoris in a randomized, double-blind parallel group study lasting 7 weeks. Twenty patients were enrolled into the trial and 16 patients completed the study. To evaluate the anti-ischemic effects of the two drugs, a treadmill exercise test was performed after a 1-week placebo run-in period and 6 weeks of treatment. On the same occasions, weekly sublingual nitroglycerin consumption and the number of anginal attacks were also recorded in the patient's diary. The total duration of exercise increased significantly with both nicorandil, 10 and 20 mg, and metoprolol (p < 0.01). Similar improvements were observed in the time to onset of ischemia with both treatments (p < 0.01). The double product at maximal comparable workload (MAX 1) was reduced with the two drugs (p < 0.05 for nicorandil and p < 0.01 for metoprolol), while at the maximal exercise time (MAX 2) it was reduced with metoprolol (p < 0.01) and slightly but not significantly increased with both doses of nicorandil. Weekly sublingual nitroglycerin consumption and anginal attacks were also significantly reduced a similar manner by both treatments (p < 0.01). In conclusion, nicorandil, 10 and 20 mg bid, exerted an anti-ischemic effect comparable with that of metoprolol in patients with stable effort angina pectoris.

Antihypertensive effects of verapamil, captopril and their combination at rest and during dynamic exercise.

In order to investigate the antihypertensive effects of verapamil (CAS 52-53-9) and captopril (CAS 62571-86-2), administered alone or in combination therapy, the blood pressure and heart rate effects of these two drugs at rest and during dynamic exercise were evaluated in a double blind study in 30 moderate or severe essential hypertensive patients. After a 30-day placebo wash-out period, 15 patients (age 60.6 +/- 8.0 years, mean +/- SD) were allocated to verapamil sustained-release treatment (120 mg b.i.d. for the first month of therapy and 240 mg b.i.d. for the second one) and 15 patients (age 58.4 +/- 10.0 years) to captopril treatment (25 mg b.i.d. and 50 mg b.i.d. for the first and second month of therapy, respectively). At low dosage both verapamil and captopril significantly (p less than 0.001) and markedly reduced blood pressure values. Goal diastolic blood pressure of 90 mmHg was achieved in 40% and 20% of patients in the verapamil group and in the captopril group, respectively, at high dosage. In contrast to captopril, verapamil induced a significant and dose-dependent heart rate reduction and markedly attenuated the pressor and tachycardiac responses to dynamic exercise. The combination of verapamil 240 mg b.i.d. plus captopril 50 mg b.i.d. was then administered to patients, whose blood pressure was not satisfactorily controlled by monotherapy. This regimen allowed a better blood pressure control both at rest and during exercise than on monotherapy and induced a complete blood pressure normalization in 62% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic interactions between diuretics and calcium antagonists in the treatment of hypertensive patients.

To investigate the hypotensive and hemodynamic effects of plain and extended-release (ER) formulations of felodipine added to a diuretic in the treatment of moderate essential hypertension, we studied 18 patients in a randomized, double-blind, cross-over study. Blood pressure (BP), heart rate (HR), hemodynamics (bioimpedance), foot volume (Archimedes' principle), and symptoms were evaluated after a 1-month placebo washout, after 1-month's treatment with a fixed combination of hydrochlorothiazide 50 mg plus amiloride 5 mg (HA), and then after felodipine 5 mg twice daily (F) or felodipine ER 10 mg daily (FER) (double-blind phase), each given for 2 weeks in a randomized sequence together with the diuretic. All measurements were performed at the end of the dosing interval. At baseline, supine SBP/DBP was 175.6 +/- 12.9/113.4 +/- 8.1 mmHg; HR was 77.3 +/- 7.0 beats/min; CO was 5.3 +/- 1.4 l/min; SVR was 2166 +/- 707 dynes sec. cm5, and foot volume was 433 +/- 195 ml (FV). HA induced a reduction (p less than 0.05) in BP; one patient had a DBP = 90 mmHg and was excluded from the combination study; eight patients had a DBP reduction of greater than or equal to 10 mmHg (responders), and their blood pressure was mainly reduced by a fall in SVR. HR, CO, and FV were unchanged. The addition of felodipine to a diuretic induced a further significant (p less than 0.001) reduction in BP with respect to HA alone, with no differences between F and FER. All patients had a DBP fall greater than 10 mmHg, which had no relationship to their response to the diuretic.(ABSTRACT TRUNCATED AT 250 WORDS)

Effort blood pressure control in the course of antihypertensive treatment.

In 30 patients with mild hypertension (diastolic blood pressure, 95 to 105 mmHg), the antihypertensive effect of rilmenidine 1 mg was compared in a double-blind study, with the effect of hydrochlorothiazide 25 mg. Patients not satisfactorily controlled received a combined therapy on the same doses of the two drugs used. Rilmenidine and hydrochlorothiazide induced a significant reduction (p = 0.01) of supine and erect systolic/diastolic blood pressure 23 hours after drug intake with no change in heart rate. This effect was due to a reduction in cardiac output (bioimpedance method) significant (p = 0.05) only for rilmenidine. Both drugs controlled the increase of effort systolic blood pressure in comparison with placebo on systemic vascular resistance treadmill exercise testing. Effort cardiac output was increased by each treatment in comparison with baseline values. Both at rest and on exertion, there was no effect on systemic vascular resistance induced by the two drugs. In a second group of 10 patients with moderate hypertension (diastolic blood pressure, 105 to 115 mmHg), rilmenidine 1 mg was administered in order to evaluate its efficacy and hemodynamic effects (bioimpedance and radionuclide ventriculography), at rest and during a lying cycloergometer effort test. The drug induced a significant decrease in blood pressure at rest and on exertion four hours after drug intake. This effect was due to a reduction (p = 0.05) in systemic vascular resistance, whereas cardiac output and heart rate remained unchanged. Our results show that the reduction in systolic/diastolic blood pressure induced by rilmenidine 1 mg is comparable with that induced by the well-known antihypertensive drug hydrochlorothiazide in mild hypertension. In moderate hypertension, the 1-mg dose appears to be insufficient in controlling the blood pressure in all patients. The drug exerts its antihypertensive effect through the normalization of the altered hemodynamic parameters of hypertension (high cardiac output and/or increased systemic vascular resistance). Rilmenidine also respects the physiologic increase in blood pressure and cardiac output on exertion.

Treatment of hypertensive patients with ventricular arrhythmias: comparison and combination of beta-blocker and anti-arrhythmic therapy.

The effect of therapy with atenolol and tocainide, separately or in combination, was studied in 20 patients with hypertension and concomitant ventricular arrhythmias. Patients were given 400 mg tocainide, three times daily, 100 mg atenolol, once daily (plus 25 mg hydrochlorothiazide and 2.5 mg amiloride diuretics if required) and a combination of these treatments. Tocainide alone significantly reduced the incidence of ventricular arrhythmias without affecting atrial arrhythmias. It also controlled exercise-induced arrhythmias in 7/13 (54%) patients. Atenolol significantly reduced atrial arrhythmias and had a good effect on exercise-induced arrhythmias (reduced in 75% of patients), but it did not have a significant effect on ventricular arrhythmias. In 13 patients, despite normalization of blood pressure by atenolol, it was necessary to combine antihypertensive therapy (atenolol) with anti-arrhythmic therapy (tocainide) in order to reduce ventricular arrhythmias. All drugs were well tolerated. It is concluded that, in certain patients, specific anti-arrhythmic treatment may be necessary to control ventricular arrhythmias in hypertensive patients despite normalization of blood pressure by beta-blockers.

Atenolol and amiodarone: a comparative study of their anti-ischaemic effect.

A total of 10 patients with mixed angina were entered into a study to compare the anti-ischaemic efficacy of atenolol and amiodarone. The study was divided into three parts: (a) placebo for 2 weeks; (b) 100 mg atenolol given for 8 weeks; and (c) amiodarone given for 8 weeks, divided into week 1, 200 mg three times daily; week 2, 200 mg twice daily; weeks 3 and 4, 200 mg once daily; weeks 5-8, 200 mg once daily for 5 days a week. Clinical examination, basal and multi-stage effort electrocardiograms were performed at the end of each treatment. The number of anginal attacks and the amount of trinitrin taken by the patients were significantly reduced by both drugs with no significant difference between them. Compared with placebo, both drugs induced a significant increase in work capacity and in the time to decrease the ST-segment by 1 mm. At rest, atenolol reduced systolic blood pressure, heart rate and the systolic blood pressure--heart rate product compared with placebo. Systolic blood pressure was also reduced significantly compared with patients given amiodarone. Amiodarone did not influence these parameters. At maximum effort, amiodarone reduced heart rate and the systolic blood pressure--heart rate product compared with placebo. This reduction was greater for atenolol. The ST-segment depression was comparable between patients given either test drug. Amiodarone, therefore, exerts an anti-ischaemic effect similar to that shown by atenolol with different haemodynamics: atenolol reducing myocardial oxygen demand, amiodarone having an additive increase of coronary flow. Such an effect was obtained with a lower dose of amiodarone than is commonly used.

Bisoprolol in the treatment of angina pectoris: a double blind comparison with verapamil.

In order to verify the anti-ischaemic effect of a new beta-blocking agent, bisoprolol, a double blind parallel groups trial was carried out in comparison with verapamil. 26 patients with a history of spontaneous and/or effort angina were studied. After a two-week treatment with placebo, they were randomized in two groups. One group was treated for 4 weeks with bisoprolol 10 mg o.d. and for the following 4 weeks with bisoprolol 20 mg o.d. The other group received verapamil 80 mg t.i.d. for the first 4 weeks and 120 mg t.i.d. for the remaining 4 weeks. Throughout the study isosorbide dinitrate 20 mg b.i.d. was administered and sublingual nitroglycerin was allowed when necessary. 21 patients completed the study. Both bisoprolol and verapamil significantly reduced the number of angina episodes and nitroglycerin tablets consumption, as well as ischaemic episodes recorded on Holter ECG. The total number and severity of ectopic ventricular beats were reduced too. On multistage treadmill exercise test, both drugs increased effort time and time to ST depression = 1 mm, and reduced ST depression and double-product. The effect of bisoprolol on double product was greater than that of verapamil because of the better control of heart rate. The relationship ST/double product suggested that beta-blockers act essentially through the reduction of myocardial oxygen consumption and verapamil possibly with an additive effect on coronary circulation. Radionuclide ventriculography showed no deterioration of rest ventricular function with both drugs. In conclusion, bisoprolol and verapamil showed a satisfactory anti-ischaemic effect, with good tolerability.

Is the carcinoembryonic antigen test a valid predictor of response to medical therapy in disseminated breast cancer?

In 30 of 63 patients with disseminated breast cancer, CEA became positive before medical therapy. Treatment response was obtained in 63.3% of CEA-positive patients compared to 15.2% of CEA-negative patients. The CEA-positive patients also had a longer relapse-free survival, a longer survival from diagnosis of metastases, and a longer overall survival from primary surgery than CEA-negative patients. CEA production appears to be an important and favorable prognostic factor in disseminated breast cancer and determinant of treatment response.

The role of carcinoembryonic antigen in the postmastectomy follow-up of primary breast cancer and in the prognostic evaluation of disseminated breast cancer.

Serum levels of carcinoembryonic antigen (CEA) were evaluated in 145 patients with breast cancer. There were 107 patients with "indolent" disease: 8 had previous metastases in complete posttherapeutic remission and were CEA-negative; CEA became positive in 2 of 3 of these cases who subsequently relapsed. The other 99 patients were without clinical evidence of disease after mastectomy. Of these, 82 were disease-free and CEA-negative, 2 relapsed and simultaneously became CEA-positive, 4 had recurrences but remained CEA-negative, 4 became CEA-positive but without clinical signs of metastases, and 7 became CEA positive before the clinical-instrumental diagnosis of metastasis. CEA was positive in 23 of 38 patients (60.5%) with "active" disease. Response to medical therapy occurred in 6.6% of CEA-negative patients compared to 55.0% of CEA-positive patients. Among CEA-positive patients, there was a similar percentage of response to medical therapy in patients with small (50.0%) or large (56.5%) tumor burden. A response to medical therapy was observed in all patients with a disease-free interval equal to or greater than 24 months and CEA-positive.

Acebutolol and nifedipine in the treatment of arterial hypertension: efficacy and acceptability.

The antihypertensive efficacy and the acceptability of nifedipine (NI, Adalat) and the usefulness of its combination with a beta 1-selective blocking drug, acebutolol (AC), were studied in a placebo controlled trial on 15 patients with moderate hypertension. The study consisted of three phases: 1. An acute test, including the single blind comparison of three different single doses of NI (5, 10, 20 mg), alone and in combination with AC 200 mg, with placebo and with AC alone (200 mg), showed an early hypotensive effect, with no differences for the three doses of NI, reaching the maximum between 50 and 240 min, greater than the one of AC, and smaller in comparison with the one of the combinations, which didn't differ at the three doses of NI. Heart rate (HR) and side effects, instead, increased with the increasing doses of NI, suggesting a worse acceptability for the greater doses. 2. A long-term treatment, including a double-blind comparison of three separate periods of 4 weeks of treatment with NI (10 mg three times a day), AC (200 mg three times a day) and with the combination of the same doses, showed a significant reduction of systolic and diastolic blood pressure (BP) for each treatment, not significantly different at rest for the three single drugs but greater for the combined treatment, assuring also a better control of systolic BP during exercise. A reduced number of side effects was seen with the combined therapy which seems to contribute to a better compliance.(ABSTRACT TRUNCATED AT 250 WORDS)