Ettore Bichisao

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.

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

Abstract 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 (El) and estradiol (E2) to the limit of sensitivity methods, and plasma estrone sulfate (EIS) 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 ≥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.

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.

Merkel cell carcinoma after liver transplantation : A case report

Background 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. Methods and results 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. Conclusion 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.

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.

Current treatments of neuroendocrine tumors role of biotherapy and chemotherapy.

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-α and somatostatin analogues, and chemotherapy. Somastostatin analogues are widely used in patients with symptoms and with carcinoids of low differentiation grade. Interferon-α 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.

Aminoglutethimide in advanced breast cancer: plasma levels and clinical results after low and high doses

SummaryDrug plasma levels, metabolism data and clinical results were evaluated after the daily administration of either 500 or 1,000 mg aminoglutethimide (AG, Orimeten, Ciba-Geigy) plus hydrocortisone acetate (20 mg b. i. d.). A total of 34 patients with advanced breast cancer entered the study: 17 were given 1,000 mg/day and 17 received 500 mg/day for at least 3 months. A novel HPLC method was developed to determine the levels of AG and its known metabolites [N-acetyl-AG (NAG), formyl-AG, nitroglutethimide, hydroxy-AG] in the biological samples. AG plasma concentration was significantly higher during the 1,000-mg/day regimen. NAG was the only metabolite observed in plasma, always occurring at concentrations lower than those of the parent drug. The ratios between NAG and AG levels distinguish two statistically different groups of patients. Irrespective of the dose, a partial response was observed in 44% of the patients; no change in 32% of cases; and progressive disease had an incidence of 24%. The probability of response was not dependent on the drug AUC or on the NAG/AG ratio and did not significantly depend on previous hormone treatment. Neither the plasmatic level of the AG or metabolite concentrations nor the NAG/AG ratio seemed to affect the incidence of side effects.

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.