[Show abstract][Hide abstract] ABSTRACT: Neuroendocrine tumors of an unknown primary site are rarer than other neuroendocrine tumors (0.6-2% of all neuroendocrine tumors) and have a poor prognosis. The aim of the study was to review the cases of unknown primary site neuroendocrine tumors encountered at the Istituto Nazionale Tumori of Milan between 1984 and 2008 in order to verify their incidence and evaluate their characteristics and prognosis.
During the study period, 750 neuroendocrine tumor patients attended our Institute, 82 of whom (10.9%) were diagnosed as having neuroendocrine tumors of an unknown primary site. The data from their medical records were analyzed descriptively, and survival probabilities were calculated using the Kaplan-Meier method and the logrank test, considering patient, tumor and treatment-related characteristics.
The 82 patients with neuroendocrine tumors of an unknown primary site (34 males) had a median age of 60 years; 57 (69.5%) had histologically well-differentiated tumors, 3 (3.7%) poorly differentiated tumors, and 22 (26.8%) had tumors that could not be classified. Of the 52 patients (62.2%) who underwent Octreoscan® (Bykgulden Italia SpA), 40 (78.4%) showed a pathological uptake and 11 (21.6%) were negative. Thirty-one patients (37.8%) underwent metastatic site surgery, which was radical in 11 cases (35.4%). Forty-eight patients (58.5%) received somatostatin analogues, and 41 (50.0%) underwent chemotherapy. At the end of the study period, 59 patients (72.0%) had died, 31 (53.0%) because of disease progression, and 23 (28.0%) were still alive.
Neuroendocrine tumors of an unknown primary site are difficult to identify but their incidence is higher than previously reported, and the prognosis remains unfavorable.
[Show abstract][Hide abstract] ABSTRACT: A phase III trial assessed the efficacy of palonosetron plus dexamethasone given once in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) following a broad range of moderately emetogenic chemotherapy (MEC) regimens.
This multicentre, randomized, open-label, non-inferiority trial evaluated two different treatment groups. One group received palonosetron (0.25 mg intravenously) and dexamethasone (8 mg intravenously) before chemotherapy, while the other was administered the same regimen on day 1 followed by dexamethasone 8 mg orally on days 2 and 3. The primary endpoint was complete response (CR; defined as no emetic episodes and no rescue medication) during the overall phase (days 1-5 after chemotherapy initiation). The non-inferiority margin was predefined as a 15% difference between groups in the primary endpoint.
Of 332 chemotherapy-naïve patients included in the intention-to-treat analysis, 65.1% were female, and 35.2% received anthracycline plus cyclophosphamide (AC)-based regimens. Overall CR rates were 67.5% for those administered dexamethasone only on day 1 (n = 166), and 71.1% for those also administered dexamethasone on days 2 and 3 (n = 166; difference -3.6% (95% confidence interval, -13.5 to 6.3)). CR rates were not significantly different between groups during the acute (0-24 h post-chemotherapy; 88.6% versus 84.3%; P = 0.262) and delayed phases (days 2-5; 68.7% versus 77.7%; P = 0.116).
Palonosetron plus single-dose dexamethasone administered before common MEC regimens provide protection against acute and delayed CINV which is non-inferior to that of palonosetron plus dexamethasone for 3 days. However, the major benefit of the single-day regimen occurs in patients receiving non-AC MEC regimens.
Preview · Article · Aug 2011 · Supportive Care in Cancer
[Show abstract][Hide abstract] ABSTRACT: The aim of this trial was to evaluate the safety and efficacy of oxaliplatin and capecitabine (XELOX) in neuroendocrine tumours' (NETs) treatment.
Forty patients (pts) with advanced NETs were treated. Of these, 13 had untreated poorly differentiated NETs, 27 had well-differentiated NETs in progression after somatostatin analogues. Patients received oxaliplatin e.v. 130 mg/mq i.v. and capecitabine 2,000 mg/mq/die. The primary sites of the disease were: lung (10 pts), pancreas (15 pts), small bowel (8 pts), unknown (1 pt), others (6 pts).
In 13 pts with poorly differentiated NETs objective responses (OR) were: 3 PR (23%), 1 SD (7%), 9 PD (70%). Biochemical responses were 11%. In 27 patients with well-differentiated NETs the OR were: 8 PR (30%), 13 SD (48%) and 6 PD (22%). Biochemical and symptomatic responses were 20 and 50%, respectively.
The XELOX regimen is effective and tolerated in well-differentiated NETs after progression following somatostatin analogues.
No preview · Article · May 2007 · Cancer Chemotherapy and Pharmacology
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Full-text · Article · Sep 2005 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: Merkel cell carcinoma is a rare and aggressive neuroendocrine skin cancer with a very low incidence in the general population. MCC seems to be common in transplant recipients and 52 cases have been reported in the literature.
This report describes a Merkel cell carcinoma which developed in a liver transplant recipient. To our knowledge, this is the second such case reported, as Merkel cell carcinoma most commonly occurs after kidney and heart transplants. The treatment approach is described and the literature on the subject is reviewed.
There is currently no consensus regarding the optimal therapeutic approach to Merkel cell carcinoma. In transplant recipients, such tumors are more common and more aggressive but their treatment does not differ from the treatment of Merkel cell carcinomas in the general population.
[Show abstract][Hide abstract] ABSTRACT: In postmenopausal patients, estrogens have an important role in breast cancer growth and aromatase inhibitors (AI) suppress the aromatase enzyme system which converts androgens into estrogens. The aim of this study was to evaluate the effect on estrogen suppression of formestane 250 mg i.m. fortnightly, given immediately after the failure of a previous treatment with non-steroidal AI. Twenty-two advanced breast cancer patients progressing on letrozole, anastrozole and aminoglutethimide entered the study. At the beginning of the study, the serum estrogen levels were suppressed by the previous treatment with non-steroidal AI, and the following treatment with formestane moderately maintained this suppression; in four patients serum estrogen levels increased fivefold after 10 weeks. Neither complete nor partial responses were observed; 11 patients (50%) showed a stable disease lasting > or = 6 months, and the median time to progression was 6 months (range 3-9 months). No correlation was observed between clinical responses and serum estrogen suppression. Tolerability was satisfactory, and no patient withdrew from the study due to adverse events. In conclusion, formestane has demonstrated a moderate activity in estrogen suppression, and there is evidence that, at the failure of a previous treatment with non-steroidal AI, the sequential use of steroidal AI is feasible. This approach can be used in clinical practice in order to offer a disease control with a satisfactory quality of life.
No preview · Article · May 2004 · Biomedecine [?] Pharmacotherapy
[Show abstract][Hide abstract] ABSTRACT: Neuroendocrine tumors are rare neoplasms originating from cells belonging to a diffuse or confined neuroendocrine system and characterized by a significant histopatologic and biologic heterogeneity. Timely diagnosis is delayed because they are often clinically silent for their low differentiation grade and the absence of any symptom due to abnormal hormone release. For these reasons, many neuroendocrine tumor patients are not treated medically for metastatic or inoperable disease. Medical treatments include biotherapy, with interferon-alpha and somatostatin analogues, and chemotherapy. Somastostatin analogues are widely used in patients with symptoms and with carcinoids of low differentiation grade. Interferon-alpha is used alone or in combination with somatostatin analogues. Chemotherapy is active in patients with poorly differentiated neuroendocrine tumors. The therapeutic regimen commonly used is the combination of cisplatinum and etoposide. In conclusion, no standard treatment for NET has yet been identified, and the response criteria suggested by ITMO remain a reference point. The clinical aspect of the disease and biologic features suggest the identification of neuroendocrine tumors patients suitable for the appropriate therapies. On these bases, it is recommended that diagnosis and treatment of neuroendocrine tumors be carried out at specialized oncological centers involved in clinical trials.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Apr 2000 · The quarterly journal of nuclear medicine: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR)
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Mar 2000 · Critical Reviews in Oncology/Hematology
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Mar 1999 · European Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: 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, 0.5mg versus 2.5mg 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 0.5mg and 24 on 2.5mg. 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, 17α-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 0.5mg and after 2 months at 2.5mg. In conclusion, both letrozole doses suppressed oestrogen levels without affecting adrenal activity.
No preview · Article · Feb 1999 · European Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Nov 1997 · The Journal of Steroid Biochemistry and Molecular Biology
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Jul 1997 · International Journal of Oncology
[Show abstract][Hide abstract] ABSTRACT: 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.