Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment?

BACKGROUND: Neuroendocrine tumours (NETs) are a rare and heterogeneous group of neoplasms. The most recent WHO classification provides clinical tools and indications to make the diagnosis and to suggest the correct treatment in different subgroups of patients. The aim of this trial was to apply the new classification criteria in clinical practice and, accordingly, to choose the most appropriate treatment. PATIENTS AND METHODS: Thirty-one evaluable patients, not previously treated, classified as advanced well differentiated NETs according to the new classification, were given long-acting release octreotide 30 mg every 28 days until evidence of disease progression. The treatment activity was evaluated according to objective, biochemical and symptomatic responses. Safety and tolerability were also assessed. RESULTS: Two partial objective tumour responses were obtained (6%), stabilization occurred in 16 patients (52%) and 95% of patients had a disease stabilisation lasting > or =6 months. However, eight patients showed rapid disease progression within 6 months of therapy and six patients after 6 months. Biochemical responses, evaluated by changes in serum chromogranine A levels were reported in 20/24 patients (83%). Symptomatic responses were observed in 6/14 patients (43%): a complete syndrome remission in one patient, partial syndrome remission in five patients, no change in four patients and progressive disease in four patients. The median overall survival was not reached, and the median time to disease progression was 18 months (range 1-49 months). The treatment was well tolerated, no severe adverse events were observed and no patient withdrew from the study because of adverse events. CONCLUSIONS: The WHO classification enables identification of low-grade NET patients who may be suitable for hormonal treatment. Octreotide LAR was seen to be effective in controlling the disease and was well tolerated. However, eight patients failed to respond to the treatment, despite histological evidence of a well differentiated tumour according to the new classification. This suggests that further histological examination should be carried out, especially in patients with visceral metastases and a short disease-free interval.

c-erbB 2 serum level as prognostic factor in hormonally treated advanced breast cancer patients.

To investigate whether c-erbB 2 serum levels may be predictive of clinical response, progression-free and overall survival in postmenopausal women with advanced breast cancer hormonally treated, 265 patients enrolled in previous clinical trials were evaluated. C-erbB 2 serum levels were assessed before the start of treatment and in a subgroup of patients also at the first response evaluation. In addition, serum CA 15.3 levels were determined. The role of c-erbB 2 was investigated by means of multiple regression models in which both c-erbB 2 and CA 15.3 values were modelled as continuous variables together with other known prognostic factors. The failure probability tended to be higher in the presence of high c-erbB 2 levels, but the trend was not statistically significant; in contrast, significant results were obtained for progression-free survival (PFS,P <0.001) and overall survival (OS, P=0.014). The within-patient c-erbB 2 variation significantly predicted PFS (P=0.006) and OS (P=0.040). It is worth noting that c-erbB 2 and CA 15.3 baseline levels were significantly correlated and that the prognostic effect of c-erbB 2 tended to disappear in the presence of high CA 15.3 levels for PFS and OS.

Tumor response and estrogen suppression in breast cancer patients treated with aromatase inhibitors.

BACKGROUND: The rationale for the hormonal treatment of breast cancer (BC) is based on depriving tumor cells of estrogenic stimulation. Aromatase inhibitors (Als) block the conversion of peripheral tissue androgens to estrogens with different levels of potency. In an attempt to investigate the relationship between tumor response and estrogen suppression, we reviewed the hormonal and clinical data of two previous studies with formestane (250 and 500 mg i.m. fortnightly) in advanced BC patients. PATIENTS AND METHODS: Two hundred four BC patients were selected on the basis of the availability of records concerning their plasma estrone (El) and estradiol (E2) levels assessed at scheduled times. The degree of estrogen suppression and the best clinical response of each patient during the trials were considered. RESULTS: There was a positive and significant (P < 0.05) correlation between baseline and post-formestane E1 and E2 levels, with a decrease in the levels of both hormones irrespective of any antitumor response. In particular, the degree of plasma estrogen suppression was similar in the patients who experienced a complete remission and those with progressive disease (PD). CONCLUSIONS: The plasma estrogen suppression induced by aromatase inhibition is not the only mechanism accounting for its clinical activity. Many clinical trials have demonstrated that all AIs induce a similar antitumor response regardless of their potency, and further investigations are warranted in order to improve our understanding as to why the patients with PD also show a significant plasma estrogen suppression. It is possible that intratumoral aromatase activity may be a marker for selecting the BC patients most likely to respond to AI treatment.

New clinical trials for the treatment of neuroendocrine tumors.

In oncology there is an increasing interest in neuroendocrine tumors, whose incidence is generally considered low, although in a recent analysis of 5,468 cases there was an increase in the proportion of pulmonary and gastric carcinoids and a decrease in the appendiceal carcinoids. However carcinoid tumors are indolent and their diagnosis is often difficult to carry out, so the true incidence may be higher. Surgery remains the treatment of choice and it should always be considered in patients with neuroendocrine tumors although a complete cure is difficult to obtain. Cytotoxic chemotherapy is the medical treatment for highly proliferating neuroendocrine tumors, but it has showed a modest benefit. Somatostatin analogues, octreotide and lanreotide are the standard hormonal treatment for neuroendocrine tumors. Recently, two trials on lanreotide and octreotide have been published, and it is worth noting that in each trial a long-acting formulation has been used: for lanreotide a prolonged-release formulation (PR) which allows an injection of 30 mg every 2 weeks, and for octreotide a long-acting release formulation (LAR) which allows an injection of 10, 20 or 30 mg every 28 days. The results of each trial are very promising. However, there are methodological and clinical aspects which make it difficult to carry out new trials for studying neuroendocrine tumors. The increasing number of biological markers deserve further investigations before their wide use in clinical practice.

Steroidal aromatase inhibitors in elderly patients.

The choice of treatment for elderly breast cancer patients needs particular care because the presence of physiological functional impairments can modify the drug bioavailability in an unpredictable manner. Hormonal treatment remains one of the choices and, although tamoxifen has proved to be effective in any setting, the use of selective aromatase inhibitors is arousing. Depending on their chemical structure, aromatase inhibitors are either steroidal (such as exemestane and formestane) or non-steroidal (such as letrozole, vorozole and anastrozole). Formestane has been studied in elderly patients with breast cancer and has been found to induce an overall response rate of 51% (95% CI, 35-67%). The drug suppresses estradiol (E2) levels, and changes in other hormones (FSH, LH and SHBG) are observed, but with poor clinical significance, thus confirming its selectivity and potency. Formestane has also been demonstrated to be as effective as tamoxifen. Exemestane and non-steroidal aromatase inhibitors appear to be very promising drugs.

High-dose loperamide in the treatment of 5-fluorouracil-induced diarrhea in colorectal cancer patients.

Thirty-seven colorectal cancer patients with grade 1-4 diarrhea (NCICTC) caused by chemotherapy with 5-FU-containing regimens, received oral loperamide at the initial dose of 4 mg followed by 4 mg every 8 h (total dose 16 mg/24 h). Twenty-five patients (69%) were diarrhea-free and were considered to be treatment responders. Eight-four percent of the patients with grade 1 or 2 diarrhea achieved a response, but only 52% of those with grade 3-4 diarrhea. These data seem to suggest that high-dose loperamide is effective in patients with moderate diarrhea and can be regarded as the treatment of choice. The patients with more severe diarrhea did not respond so well, and should, perhaps, be given first-line treatment with more effective drugs, such as somatostatin analogues (e.g., octreotide).

Aromatase inhibitors in the treatment of postmenopausal breast cancer.

Anastrozole, letrozole and vorozole are new aromatase inhibitors with a nonsteroidal structure (NSS), and have been demonstrated to be highly effective and better tolerated than standard endocrine therapy with megestrol (megestrol acetate) and aminoglutethimide (AG). These agents are very potent and selective: all of them are capable of suppressing estrone (E1) and estradiol (E2) to the limit of sensitivity methods, and plasma estrone sulfate (E1S) levels are also suppressed. However, the fact that this potency has not led to any greater clinical efficacy, and that there is no relationship between estrogen suppression and clinical response, suggests that aromatase inhibitors may have additional mechanisms of action. A number of international, multicentre clinical trials have compared anastrozole, letrozole and vorozole with megestrol 160 mg/day or AG 500 mg/day plus hydrocortisone in patients with advanced breast cancer. Letrozole proved to be significantly more effective than megestrol but anastrozole had a greater effect on survival than either agent. However, letrozole therapy led to longer survival than that observed in patients treated with AG. The activity of vorozole was similar to that of megestrol and AG. These results have raised a number of questions. The first is how should the clinical results be evaluated, given that 'disease stabilisation lasting > or =6 months' has been considered a response? The second is how should these drugs be used, and whether there is a rationale for using them in combination or sequentially in the treatment of patients with advanced breast cancer? Finally, is the possible effect of formestane and vorozole on intratumoral aromatase an alternative or concomitant mechanism of action? Anastrozole, letrozole and vorozole will be compared with tamoxifen in postmenopausal patients with breast cancer in adjuvant and primary settings. However, we feel that concomitant biological and clinical studies should also be carried out in order to clarify the properties of these drugs and avoid possible risks for patients over time.

Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients.

Letrozole is an orally competitive aromatase inhibitor. This double-blind, randomised, multicentre trial was carried out to evaluate the endocrine effects of two doses of letrozole, 0.5 mg versus 2.5 mg orally daily, in postmenopausal advanced breast cancer patients progressing after tamoxifen. The pharmacokinetics of letrozole was also assessed. 46 patients entered the trial, 22 on letrozole 0.5 mg and 24 on 2.5 mg. A significant suppression of oestrone and oestradiol levels was achieved by both letrozole doses. Neither letrozole dose induced any changes in cortisol and aldosterone production at rest or after Synacthen stimulation. Androstenedione, testosterone, 17 alpha-OH progesterone, triiodothyronine (T3) thyroxine, (T4) and thyroid-stimulating hormone (TSH) plasma levels did not show any significant changes. Sex hormone binding globulin (SHBG), follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels increased significantly over time. Plasma letrozole concentrations increased until reaching steady-state values after 1 month at the dose of 0.5 mg and after 2 months at 2.5 mg. In conclusion, both letrozole doses suppressed oestrogen levels without affecting adrenal activity.

A multicentre, randomized, pharmacokinetic, endocrine and clinical study to evaluate formestane in breast cancer patients at first relapse: endocrine and clinical results. The Italian Trials in Medical Oncology (I.T.M.O.) group.

BACKGROUND: In postmenopausal breast cancer (BC) patients, tamoxifen (TAM) is frequently used in first-line therapy, and for those relapsing under TAM, aromatase inhibitors would be the drug of choice. Formestane, a new aromatase inhibitor, has been demonstrated to be as effective as TAM in first-line therapy. This trial was carried out to investigate the pharmacokinetics and antitumor activity of two formestane doses in BC patients at first relapse, as well as their effects on estrogen levels, evaluated by means of a new analytical method. PATIENTS AND METHODS: One hundred fifty-two postmenopausal BC patients were randomly given formestane 250 mg or 500 mg intramuscularly every two weeks. The blood samples for estrogen measurements were taken on the first day of therapy, at 4 and 10 weeks, and every 12 weeks thereafter. Tumor response was first evaluated after 2.5 months, and then every three months. RESULTS: Seventy-three patients received formestane 250 mg and 79 received 500 mg. After four weeks, plasma estrone, estradiol and estrone sulphate levels were significantly (P < 0.001) suppressed in both groups. The overall response rates were 30% and 40% on 250 mg and 500 mg, respectively. CONCLUSIONS: Both of the formestane doses are effective in reducing plasma estrogen levels in BC patients at first relapse, and the new analytical method improved the quality of results. The antitumor response was highly satisfactory.

Double-blind, multicenter, randomized trial to compare the effect of two doses of adrenocorticotropic hormone versus placebo in controlling delayed emesis after high-dose cisplatin in adult patients with cancer.

PURPOSE: To compare, in a double-blind, placebo-controlled, randomized trial, the efficacy of two different doses of the depot formulation of adrenocorticotropic hormone (ACTH) in controlling delayed emesis after cisplatin. PATIENTS AND METHODS: One hundred fifty-two patients were enrolled onto the study. On day 1, all patients received cisplatin (60 to 120 mg/m2) and a combination of dexamethasone 20 mg plus ondansetron or metoclopramide to prevent acute emesis. On day 2 (24 hours after cisplatin administration), patients were randomized to receive placebo, or ACTH 1 mg intramuscularly (I.M.), or ACTH 2 mg I.M. plus one additional dose of 1 mg on day 4. Details of vomiting, nausea, and adverse effects were recorded daily for every 24-hour period from day 2 to day 6. In a subset of patients, serum cortisol levels were measured between 20 and 72 hours after cisplatin administration. RESULTS: One hundred fifty patients were assessable. Over the 5 days of the study, delayed vomiting occurred less frequently in the patients treated with ACTH 2 mg plus 1 mg than in those treated with ACTH 1 mg or placebo (28%, 38%, and 65%, respectively; P = .001). The greatest observed differences were seen on days 2 (24 to 48 hours; P = .01) and 3 (48 to 72 hours; P = .01). On days 4, 5, and 6 (96 to 144 hours), no significant differences were observed among the three arms. The severity of delayed emesis expressed as the mean number of emetic episodes per day was 0.48, 0.70, and 0.80, respectively (P = .002). Patients treated with the higher dose of ACTH had the least nausea on day 3 (P = .02) and day 4 (P = .03). Adrenal cortisol secretion rapidly increased after ACTH injection, but was suppressed for approximately 44 hours in the placebo group. Toxicity was mild and transient in all groups. CONCLUSION: ACTH reduces the incidence and severity of delayed vomiting and nausea after cisplatin. A dose of 2 mg 24 hours after cisplatin is better than one of 1 mg. Whether the activity of ACTH is mediated only by adrenal corticosteroids needs to be verified.

The aromatase inhibitor letrozole in advanced breast cancer: effects on serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels.

Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels were measured in two groups of postmenopausal women with advanced breast cancer, who received the aromatase inhibitor letrozole 0.5 or 2.5 mg p.o. once daily. Blood samples were obtained from 15 patients in each dose group at baseline, and one and three months after starting therapy. Circulating IGF-I and IGFBP-3 concentrations were determined by means of radioimmunoassay. In both dosage groups a statistically significant increase in the IGF-I levels was observed during three months of letrozole treatment (P=0.003). In addition, the multiple testing procedure yielded in the whole patient population a significant result in the comparison between mean IGF-I values after three months of therapy and those observed at baseline (P=0.004), the estimated average increase being of 24%. No significant result was obtained in the analysis for the dose effect (P=0.077) and for the time x dose interaction (P=0.208). Circulating IGFBP-3 levels did not appear to be affected by letrozole treatment in either of the dose groups. This is the first report concerning the short-term effects of letrozole on components of the IGF system in breast cancer patients; further investigations are warranted in order to confirm these preliminary data.

Effects of aromatase complex selective inhibition on insulin-like growth factor 1 and insulin-like growth factor binding protein 3 circulating levels in breast cancer.

The aim of our study is to evaluate insulin-like growth factor (IGF) and IGF binding protein (IGFBP)-3 circulating levels in postmenopausal women treated with type I aromatase inhibitor formestane for breast cancer. Sixty-three patients at their first relapse entered the trial and were randomly given formestane at 250 mg or 500 mg i.m. fortnightly. Effects of the endocrine treatment on IGF-1 and IGFBP-3 were measured before and during therapy at scheduled times. IGF-1 and IGFBP-3 seems to slightly increase in both the dose groups, but only IGFBP-3 levels showed statistically significant fluctuation (baseline vs 4 weeks, p=0.01925; baseline vs 10 weeks, p=0.04537). These modifications are unlikely to be related to clinical status because they were observed both in responsive and unresponsive patients. This report demonstrates that hormonal treatments for breast cancer (particularly, aromatase inhibitor administration) can modify growth factor disposition to tumour.

Novel non-steroidal aromatase inhibitors: are there new perspectives in the treatment of breast cancer?

Breast cancer is the most common malignant neoplasm affecting women in Western countries, and most new cases are manifested during the postmenopausal period. The clinical results obtained with aminoglutethimide, and later with formestane, have established aromatase inhibition as one of the major therapeutic options in hormone-dependent advanced disease. Nevertheless, the lack of specificity of aminoglutethimide and the less than optimal oral activity of formestane soon led to further efforts to find a potent, highly selective, orally active, side-effect-free aromatase inhibitor for use in postmenopausal women with advanced breast cancer. Here we review the available data on three new, competitive non-steroidal aromatase inhibitors--letrozole, vorozole and anastrozole--which are approaching the point of detailed pharmacologic and clinical evaluation. Preliminary data have confirmed the high potency and selectivity of these endocrine agents, but their antitumor activity still remains to be completely defined. Challenges given by these novel aromatase inhibitors are discussed taking into account the biologic implications related to their mechanism of action and their future use in the management of breast cancer.

Activity of formestane in de novo tamoxifen-resistant patients with metastatic breast cancer.

In order to assess the feasibility of a sequential hormonal treatment after tamoxifen failure, 24 postmenopausal advanced breast cancer patients (median age 60 years; ECOG PS < or = 1) were treated with formestane (4-hydroxyandrostenedione) 250 mg i.m. fortnightly; 19 patients were estrogen receptor-positive. The sites of metastatic disease were soft tissue in 22 patients, viscera in 9 and bone in 18. The patients were considered evaluable for tumor response after four doses of formestane. Objective responses were observed in 8/24 patients (33%) with one complete and seven partial responses. The median response duration was 9.5 months. The complete response was obtained on skin. We conclude that although the number of complete responses appears to be unsatisfactory, de novo tamoxifen-resistant breast cancer patients are suitable for further hormonal treatment with formestane.

Formestane: an effective first-line endocrine treatment for advanced breast cancer.

Formestane, a new selective aromatase inhibitor devoid of severe side-effects, has been shown to be active in patients with advanced breast cancer. To investigate the clinical activity and endocrinological effects of formestane as a first-line treatment, 52 patients were administered two different doses: 24 received 250 mg formestane and 28 received 500 mg formestane i.m. fortnightly. All of the patients had a performance status of 2 or less (ECOG scale), 34 (65%) had a disease-free interval of at least 2 years and 21 (40%) were both oestrogen-receptor- and progesterone-receptor-positive; 20 patients received hormone and 13, received chemotherapeutical adjuvant treatment. Objective responses were obtained in 8 patients in the 250-mg group (33%; 95% CI: 14%-52%) and in 13 patients in the 500-mg group (46%; 95% CI: 28%-64%). The median response duration in the two groups was respectively 11 and 12 months. E2 serum levels of oestradiol had significantly (P < 0.001) decreased to more than 40% below the baseline value in both groups after 15 days of treatment, and remained unchanged thereafter. Local and systemic tolerability was satisfactory. We conclude that formestane is an effective and well-tolerated agent in previously untreated patients, and that these results should be confirmed by further studies.

Hormonal-therapy in patients with stage-iv breast-cancer at diagnosis.

The incidence of stage IV breast cancer at diagnosis is low, representing about 8% of all new cases. We report on the results obtained with a new aromatase inhibitor, formestane (500 mg i.m. fortnightly), given as a first treatment to fifteen postmenopausal patients with metastatic breast cancer. The overall response rate was 40%, with one complete remission in a patient with soft tissue and bone lesions and five partial remissions. The drug was well. tolerated and no significant systemic or local side effects were observed. We conclude that first treatment of stage IV breast cancer appears to be feasible with a hormonal drug such as formestane.

Efficacy and tolerability of 4-hydroxyandrostenedione (4-OHA) as first-line treatment in postmenopausal patients with breast cancer after adjuvant therapy.

Aromatase inhibitors are known to be effective in the treatment of advanced postmenopausal breast cancer. To assess the efficacy of the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA) as first-line treatment in patients who were either resistant to or had relapsed after adjuvant therapy, 50 eligible patients received intramuscular 4-OHA either 250 mg or 500 mg fortnightly until disease progression or severe adverse events. Of the 43 patients evaluable for clinical response (UICC criteria), 15 (36%) showed objective response (CR+PR), 6 (14%) stable disease (SD). In relation to disease site, objective responses were obtained in 55% of cases with soft tissue metastases (16/29); in 33% with visceral metastases (8/24), and in 24% with bone involvement (5/21). In relation to previous adjuvant treatment, there were eight objective responses among the 17 patients treated with chemotherapy (47%), and seven objective responses among the 24 treated with tamoxifen (29%). The treatment was well tolerated. These results support the hypothesis that adjuvant therapy, whether hormonal or chemotherapy, may make patients less responsive to subsequent treatment.

Chlorthalidone alone or in fixed combination with slow-release metoprolol in the management of arterial hypertension: a long-term study of 545 patients.

In a double-blind trial, 545 out-patients with essential hypertension received 25 mg/day chlorthalidone alone (274 patients) or in fixed combination with 200 mg/day slow-release metoprolol (271 patients) for 8 weeks. Both treatments significantly (P less than 0.001) decreased systolic and diastolic blood pressure; 45.6% of patients receiving chlorthalidone and 82.5% receiving combined therapy had a diastolic blood pressure of less than 95 mmHg. Patients not controlled by chlorthalidone or chlorthalidone plus metoprolol subsequently received chlorthalidone plus metoprolol (137 patients) or chlorthalidone plus metoprolol plus a third drug (34 patients), respectively, for 8 weeks. A total of 79.5% of patients receiving chlorthalidone plus metoprolol and 61.8% receiving chlorthalidone plus metoprolol plus a third drug had a diastolic blood pressure of less than 95 mmHg. Only 5.9% of patients experienced mild to moderate side-effects. Plasma potassium levels significantly (P less than 0.01) decreased during the first 8 weeks only. It is concluded that a diuretic alone or in fixed combination with a beta-blocker is effective in the long-term treatment of arterial hypertension.

Cefroxadine in the treatment of children affected by respiratory and ENT diseases. A multicentre study involving 1072 in-patients.

In this multicentre trial, 1072 hospitalized children, 573 boys and 499 girls (847 of whom were aged less than 6 years), affected by respiratory tract (376 patients) or ENT (696 patients) infections were treated for 10 days with cefroxadine per os, at an average dose of 650 mg/day (325 mg every 12 h corresponding to 25 mg/kg b.w.). Most patients (1047; 97.7%) completed the trial, while 25 patients were withdrawn from the study (20 patients for viral diseases and 5 for side-effects). Of the patients affected by respiratory tract infections, 361 completed the trial and 342 of them (94.7%) were cured in 6.0 days on average. Of the patients affected by ENT infections, 686 completed the trial and 649 of them (94.6%) were also cured in an average of 6.0 days. In the two groups the signs and symptoms of the disease significantly (p less than 0.001) decreased by the end of the study. Some patients (80; 7.6%) complained of side-effects, mainly gastric discomfort (4.9%), skin rash (2.2%) and glossitis (0.5%). In conclusion, cefroxadine exerts a satisfactory antibacterial action with only a few days of treatment, and it appears to be very well tolerated.

Age and blood pressure changes. A 20-year follow-up study in nuns in a secluded order.

In a prospective study, 144 white nuns belonging to a secluded monastic order and 138 white control laywomen were followed for 20 years to investigate whether living for a long time in a stress-free environment influences the effect of aging on blood pressure. Silence, meditation, and isolation from society are the distinctive features of the life-style examined. At study entry, blood pressure was not dissimilar in the nuns and the control group, but it increased over time only in the controls, with a mean slope of the regression line (beta coefficient) of 0.089 in the nuns (NS) and 2.171 in the controls (p less than 0.0001) for systolic blood pressure and of 0.054 in the nuns (NS) and 0.742 in the controls (p less than 0.0001) for diastolic blood pressure. Weight and body mass index increased similarly over time in the two groups. Family history of hypertension was not dissimilar between the groups. Serum cholesterol and triglycerides, higher at study entry in the nuns, increased similarly over time in the two groups. Twenty-four-hour urinary sodium excretion, collected randomly in both groups, did not differ over time between nuns and controls. None of the women smoked or used oral contraceptives. Educational level was higher in the control group, but subgroups of 48 nuns and 52 laywomen of comparable educational level maintained the same difference in the blood pressure trend over time as in the main cohort. Parity affected the increase of systolic, but not of diastolic, blood pressure with age among the laywomen, but nuns and no-childbirth controls maintained a significantly different blood pressure trend over time.(ABSTRACT TRUNCATED AT 250 WORDS)