Endocrine therapy of breast cancer. The experience of the Italian Cooperative Group for Chemohormonal Therapy of Early Breast Cancer (GROCTA).
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Breast Neoplasms↗
Biomedical subjects
D Amoroso
Publications and source records attributed to D Amoroso.
Mechanical deafferentation of basal forebrain-cortical pathways and neurotoxic lesions of the nucleus basalis magnocellularis: comparative effect on spatial learning and cortical acetylcholine release in vivo.
Rats were assigned to one of the following treatments: bilateral cut of basal forebrain-cortical fibers (DEAFF), ibotenic (IBO) or quisqualic (QUIS) acid lesions of the NBM and sham operations (SHAM). They were trained to perform a radial eight-arm maze task with all the paths or only four paths baited. Cortical cholinergic release measured by microdialysis in vivo and choline acetyltransferase activity were also assessed in the four lesion conditions. The results show that, in the full baited maze task, only the DEAFF group showed a severe spatial learning impairment. In the four-baited path task, the DEAFF group was still more impaired than the other groups but a performance deficit also emerged in rats with IBO lesions. Neurochemical data indicated that cortical choline acetyltransferase activity was reduced by 25% after IBO lesions, by 52% after DEAFF and by 46% after Quis lesions. However, cortical cholinergic release, which dropped in the same fashion after DEAFF or QUIS lesions, was unaffected by IBO lesions. Thus, in spite of the distinctive patterns of behaviour exhibited by the three lesioned groups, no correlation between cortical cholinergic deficiencies and spatial learning impairment was found. The similar behavioural effects produced by DEAFF and fornix sections suggests that, among the basal forebrain-cortical pathways, descending fibers projecting onto the septo-hippocampal system could exert a strong control on spatial learning performance.
Acetylcholine↗
Second-line hormonotherapy for breast cancer. Uselessness of first-line continuation.
The hypothesis that the results of second line hormonotherapy for breast cancer may be ameliorated with continuation of the first line has been explored in a randomized trial. Patients progressing under tamoxifen were randomly allocated to aminoglutethimide and hydrocortisone acetate with or without tamoxifen continuation. No difference has been observed between the two arms in terms of response rate and progression-free overall survival.
Aged↗
Mechanism of the galanin induced increase in acetylcholine release in vivo from striata of freely moving rats.
Galanin (GAL) administered intracerebroventricularly (i.c.v.) induced a strong and long-lasting increase in the basal acetylcholine (ACh) release from striata of freely moving rats only when the excitatory corticostriatal input was removed, while its effect was transient in striata of sham-operated rats. This effect was dose-dependent (0.78, 1.56 and 3.12 nmol) and was completely prevented by the GAL receptor antagonist, galantide. GAL injected locally (3.12 nmol) in deafferented striata also induced a persistent increase in ACh release although to a lower extent. The impairment of monoaminergic neurotransmission caused by alpha-methylparatyrosine or p-chlorophenylalanine, respectively inhibitors of catecholamine and serotonin synthesis, completely prevented the rise in ACh output from deafferented striata while the muscarinic antagonist, scopolamine (0.5 mg/kg, s.c.), failed to do it. The data suggest that GAL in the deafferented striatum facilitates basal ACh release through an indirect mechanism. The effect seems to be at least partly mediated by an action of GAL on specific receptors in the striata.
Acetylcholine↗
Effect of tianeptine on the central cholinergic system: involvement of serotonin.
The effect of tianeptine on in vivo acetylcholine (ACh) release from brain hemispheric regions of freely moving rats was investigated using the microdialysis technique coupled with a sensitive radioenzymatic method. Tianeptine, at the dose of 30 mg/kg i.p., reduced ACh release from dorsal hippocampi by 40% in 40 min, and induced a 30% decrease of ACh output from frontal cortices while at the doses of 10 and 20 mg/kg it had no effect. In striata the drug did not significantly affect ACh release although it showed a tendency to increase it. The ACh content in the three areas considered was not affected by tianeptine at above doses. The drug did not alter choline-o-acetyltransferase and acetylcholinesterase activities suggesting that it did not influence the cholinergic system through direct action on the ACh metabolism; furthermore, it did not influence the sodium-dependent high-affinity uptake of choline in striatum, cortex and hippocampus. Impairment of serotonergic (5-HT) neurotransmission by chemical lesion of the median raphe nucleus or by metergoline, a blocker of 5-HT receptors, antagonized the cholinergic effect of tianeptine. The involvement of the serotonergic system is specific because lesions of the noradrenergic dorsal bundle failed to prevent the inhibitory action of tianeptine. The present data suggest that 5-HT may mediate the effect of tianeptine on the cholinergic system in dorsal hippocampi.
Acetylcholine↗
Expression of GAL mRNA in rat hypothalamus: effect of frontal deafferentation and colchicine treatment.
The expression of galanin (GAL) mRNA was determined by in situ hybridization after frontal deafferentation and colchicine treatment in the rat hypothalamus. Frontal deafferentation significantly increased the signal in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and dorsomedial nucleus (DMN). Colchicine treatment induced a diffuse enhancement of GAL mRNA in hypothalamic nuclei. When the two treatments were combined there was an additivity of GAL mRNA expression in the previous hypothalamic nuclei and also in the arcuate nucleus (AN), where the single treatments did not modify the signal. These results suggest the regulation of GAL mRNA expression mediated by a multineuronal pathway, separate from the colchicine-induced GAL mRNA increase.
Afferent Pathways↗
Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, oestrogen-receptor positive breast cancer patients. An update at 7 years of the 1st GROCTA (Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group) trial.
504 evaluable node positive oestrogen receptor (ER) positive breast cancer patients were randomly allocated to receive either 5 years tamoxifen treatment or chemotherapy [six courses of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) followed by 4 courses of epirubicin] or a combination of both treatments. At a median follow-up of 5 years tamoxifen appeared to be more effective than chemotherapy, the difference being highly significant in postmenopausal women. The addition of chemotherapy to tamoxifen was not able to significantly improve the results achieved by tamoxifen alone, irrespective of menopausal status. Trends were similar even after stratification for the number of involved nodes. The protective effect of tamoxifen in terms of reduction of the odds of death increased with time and no rebound phenomena on recurrence or death has occurred so far after the completion of tamoxifen treatment. Overall, the prognostic value of number of involved nodes and of progesterone receptor (PgR) status was confirmed by multivariate analysis. However, the predictive value of PgR was lost in patients receiving tamoxifen alone. Similarly, the degree of ER positivity was not predictive of the response to tamoxifen. Tamoxifen treatment should still be regarded as the gold standard for postmenopausal ER positive patients. In younger women the antioestrogen proved to be safe and at least as effective as chemotherapy. However, the analysis of the annual risks suggests that the concurrent or the sequential use of chemotherapy and tamoxifen might represent a more appropriate treatment for this patient subset, particularly for those with four or more involved nodes. Different cut-offs of ER and PgR assays from those we have arbitrarily employed in the present analysis should probably be used to select more properly the patients who can benefit from endocrine therapy.
Adult↗
Tamoxifen and alpha interferon in advanced breast cancer.
Thirteen pretreated advanced breast cancer patients received a combination of alpha interferon 5 million IU every 2 days, subcutaneously, plus tamoxifen 10 mg 3 times daily, until disease progression. The objective response rate was 15.4%: 1 patient achieved a complete response, 1 a partial response and 11 demonstrated stable disease; half of the patients were receptor negative and/or pretreated with hormonotherapy. Durations of response were 16 and 26 months for the CR and PR patients respectively; median progression-free survival was 4 months (range 0-26). Toxicities were registered according to WHO criteria: 4 patients stopped the treatment with interferon because of severe flu-like symptoms, while in the others the combination was generally accepted with good tolerance.
Adult↗
Continuous venous infusion of vinblastine in metastatic breast cancer.
In 19 patients with advanced pretreated breast cancer, vinblastine was administered by continuous venous infusion (2 mg/m2/24 h for 120 h every 3 weeks), using a totally implanted venous access and a portable pump. A total of 55 courses were given. Five objective responses were observed. Drug-related toxicity consisted mainly of leukopenia (4 patients), fever (4 patients) and nausea and vomiting (3 patients). Catheter-related toxicity was observed in 4 patients (21%) and consisted of infection of the skin pocket in 1 patient and dislodging of the needle with drug extravasation in 3 patients.
Adult↗
Oral chemotherapy with idarubicin plus cyclophosphamide in advanced breast cancer.
An oral chemotherapy schedule based on idarubicin and cyclophosphamide was evaluated in 31 advanced breast cancer patients. Out of 27 patients evaluable for response, 1 (3.7%) achieved a complete response and 5 (18.5%) a partial response, with an objective response rate of 22.2% (95% confidence limits 8.6-42.3%). The median time to progression was 7 months (range 3-12). Fourteen patients (51.9%) showed a disease stabilization, and 7 progressed (25.9%). Toxicity was mild. Considering the low response rate, but also the advantages of oral chemotherapy and the mild toxicity observed, oral idarubicin plus cyclophosphamide can be considered as a second-choice regimen in advanced breast cancer.
Administration, Oral↗
Lonidamine in metastatic breast cancer.
Lonidamine belongs to a new class of antineoplastics agents, since it does interfere with cell energy processes. When administered as single agent in metastatic breast cancer, it produces moderate therapeutic effects. The pattern of toxicity includes myalgias, asthenia, testicular pain, and gastrointestinal discomfort. No myelosuppression was demonstrated in phase I-II studies. Since the peculiar mechanism of action and side effects are not overlapping with those of standard chemotherapeutic agents, combination of lonidamine with chemotherapy is currently under investigation in advanced breast cancer. Moreover, the potentiation of radiotherapy by lonidamine could be of interest in palliating symptomatic lesions from breast cancer.
Antineoplastic Agents↗
Decrease in [3H]hemicholinium binding to high-affinity choline uptake sites in deafferented striatum: restoration by oxiracetam.
Frontal cortical deafferentation of the rat striatum reduces the tone of striatal cholinergic neurons. We used biochemical and autoradiographic techniques to investigate whether the [3H]hemicholinium-3 ([3H]HCh-3) binding to sodium-dependent high-affinity choline uptake sites was influenced by this lesion. Frontal deafferentation produced a reduction of about 30% in the number of [3H]HCh-3 binding sites (Bmax) in striatum, with no significant changes in the binding affinity (Kd). Autoradiography showed a significant reduction of [3H]HCh-3 binding sites in the anteromedial portion of the striatum, but not in the posterior part of frontal deafferented rats. Oxiracetam (100 mg/kg), a nootropic drug, did not affect the distribution of [3H]HCh-3 binding sites in sham-operated rats but completely overcame the reduction in the number of [3H]HCh-3 binding sites in deafferented striatum.
Afferent Pathways↗
Megestrol acetate: phase II study of a single daily administration in advanced breast cancer.
A new formulation of megestrol acetate, a semisynthetic oral progestin used in the hormonal treatment of breast cancer, allows the administration of 160 mg of the drug in a single daily dose. Sixty-nine postmenopausal patients with advanced breast cancer have been treated with this regimen: five patients received megestrol acetate as first-line treatment of their metastatic disease, while all the others had been previously treated with one or more regimens of chemotherapy and/or hormone therapy. The median duration of the treatment for evaluable patients was 3 months (range 1-13+). Among 65 evaluable patients 2 complete responses and 12 partial responses (objective response rate 21.5%; 95% confidence limits 12.31%-33.49%) were observed. Median duration of response was 7 months (range 2-12+). Responses were observed both in visceral and in non-visceral sites of disease. Twenty-nine patients obtained a stabilization of disease (44.7%), and twenty-two progressed (33.8%). Median duration of stabilization was 4 months (range 3-13+). Median survival for all patients from the start of megestrol acetate was 9 months (range 1-22+). The most common side effect of therapy was weight gain, occurring in 36% of patients. Megestrol acetate on a single-daily-dose schedule can be considered as an interesting hormonal treatment for advanced breast cancer, especially in the clinical instance of patients who, after having obtained a remission or stabilization of disease with tamoxifen, need further palliative treatment.
Body Weight↗
Cisplatin and recombinant alpha interferon in advanced breast cancer.
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Breast Neoplasms↗
Treatment with oxiracetam or choline restores cholinergic biochemical and pharmacological activities in striata of decorticated rats.
Interruption of the corticostriatal pathway by undercutting the frontal cortex resulted after 2 weeks in a 40% reduction of basal acetylcholine (ACh) release in vivo, and in inhibition of the striatal sodium-dependent high-affinity uptake of choline (SDHACU) to the same extent. The lesion, too, completely prevented the rise (about 35%) in striatal ACh content induced by oxotremorine and apomorphine acting at muscarine and dopamine receptors, respectively. Acute intraperitoneal injections of 100 mg/kg of either oxiracetam or choline chloride resulted in time-dependent recovery of ACh output from the striata of decorticated rats to control levels. Oxiracetam also normalized the ex vivo striatal SDHACU activity of decorticated rats 2 h after administration without any effect in sham-operated rats. Oxiracetam or choline chloride administered before oxotremorine (0.8 mg/kg, i.p.) or apomorphine (1 mg/kg, i.p.) reinstated the ACh-increasing effect of these agonists. It is suggested that choline chloride acts directly simply by being the precursor for ACh, whereas oxiracetam may act indirectly, possibly by increasing the availability of choline chloride for ACh synthesis. Furthermore, the frontally decorticated rat could constitute a useful model for studying means to restore the deficit in striatal cholinergic neurotransmission.
Acetylcholine↗
Phase II study of lonidamine in metastatic breast cancer.
Thirty patients with previously treated metastatic breast cancer were entered in a phase II study with oral lonidamine. Twenty-eight patients are evaluable for toxicity and 25 for response. A partial remission was obtained in four patients (16%) and disease stability in 11 (44%): 10 patients progressed (40%). Toxicity was acceptable, consisting mainly of myalgias (39% of patients) and asthenia (21.4%). No myelotoxicity was observed. The drug is active in previously treated metastatic breast cancer and, because of its peculiar pattern of action and toxicity, deserves to be evaluated in combination with cytotoxic chemotherapy.
Adult↗
Impact of administration-related factors on outcome of adjuvant chemotherapy for primary breast cancer.
The survival of 229 patients treated with adjuvant i.v. cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) after surgery for primary breast cancer was analyzed according to three administration-related factors: total number of cycles received, time elapsed between surgery and start of chemotherapy, and dose intensity of treatment. All parameters were found to be significantly associated with survival of patients in a univariate analysis. Multivariate analysis confirmed the independent prognostic importance of dose intensity and time between surgery and chemotherapy. Although prospective studies are needed to confirm such results, clinicians should be aware that unnecessary treatment delays or dose reductions in adjuvant chemotherapy for breast cancer are probably detrimental to patient survival.
Adult↗
The role of surgery in the combined treatment of locally advanced breast cancer.
Sixty patients with stage IIIA and IIIB breast cancer have been treated with a combined modality approach including induction chemotherapy, surgery and adjuvant chemotherapy: 74.5% of patients achieved an objective response after 3 cycles of induction chemotherapy, and 98.3% of patients were rendered disease-free after induction chemotherapy and surgery or radiotherapy; at 4 years, actuarial survival and disease-free survival are 71.5% and 43%, respectively. These results are significantly better than our historical control, and locally advanced breast cancer must now be considered a curable disease when treated with an aggressive multimodal approach.
Adult↗