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C Noberasco

Publications and source records attributed to C Noberasco.

17 recordsLinked to original sources
PubMed2004

Phase II studies of BBR3464, a novel tri-nuclear platinum complex, in patients with gastric or gastro-oesophageal adenocarcinoma.

BBR3464, a novel tri-nuclear platinum complex, forms long-range DNA adducts and is highly potent when compared with cisplatin in vitro. Preclinical studies demonstrated activity in cisplatin-resistant tumours and tumours with mutated p53 status. Phase I & II clinical studies gave preliminary indications of activity in melanoma, pancreatic, lung and ovarian cancers. The aim of this study was to determine the efficacy and confirm the toxicity of BBR3464 when given either as first- or second-line treatment for advanced disease in patients with gastric and gastro-oesphageal adenocarcinoma. Two multicentre, open label, Gehan design studies were conducted; one study used BBR3464 as first-line and the other as second-line treatment for metastatic or locally advanced disease. Nineteen first-line and 26 second-line patients were enrolled receiving a total of 74 and 53 infusions, respectively. Initially, seven patients in the second-line study received BBR3464 using the planned schedule of 1.1 mg/m2 every 4 weeks; however, 5 of these patients experienced dose-limiting grade 3 or 4 febrile neutropenia; subsequent patients in both studies were treated using the modified schedule of 0.9 mg/m2, every 21 days. In 1 of 17 evaluable, previously untreated patients, regression of multiple skin lesions was noted with stabilisation of lung metastases and maxillary sinus mass, lasting 155 days. In the first-line study, the median time to progression was 85 days [95% Confidence Interval (CI): 42, 127] (2.8 months) and in the second-line study, the median time to progression was 71 days [95% CI: 42, 109] and 38 days [95% CI: 32, 73] in the 1.1 and 0.9 mg/m2 dose level groups, respectively. Toxicity data were available for 45 patients. Neutropenia was the main toxicity seen (G3: 40%, G4: 40%). Febrile neutropenia was observed in six patients (15%) treated with 0.9 mg/m2 compared with five patients (71%) treated with 1.1 mg/m2 BBR3464. Other drug-related toxicities (G3/4) included: anaemia, thrombocytopenia, nausea, vomiting, diarrhoea, mucositis and fatigue. Diarrhoea and nausea/ vomiting were adequately controlled by the use of loperamide and antiemetics, respectively. Recruitment to the second-line study was closed early due to the poor response rate (1/17 evaluable, 6%; 95% CI: 1%, 27%) and short time to progression noted in the first-line study. Further studies with BBR3464 in this tumour type are not recommended.

Adenocarcinoma↗
PubMed1999

Prediction of response to primary chemotherapy for operable breast cancer.

The use of primary systemic cytotoxics leads to a high remission rate in patients with breast cancer. Response was identified as an important variable associated with survival. Thus, features which predict response, are potentially relevant for planning treatments and improving survival. Retrospectively, we investigated several histopathological features (expression of oestrogen and progesterone receptors, Mib1, bcl-2, c-erbB-2, and p53) prior to two programmes of either sequential preoperative chemotherapy (doxorubicin plus cyclophosphamide) and radiotherapy (Group A), or preoperative chemotherapy (5-fluorouracil, folinic acid and vinorelbine) alone (Group B) in patients with operable breast cancer. After three courses, patients with a partial or complete response were given a further three courses, which was followed for patients in Group A by radiotherapy 50 Gy plus a boost of 10 Gy. All patients were submitted to surgery after completion of preoperative treatment and pathology material from 73 patients (median age, 49 years, range, 30-70; performance status, 0-1; 68 T2, 5 T3) was obtained. The overall response rate according to radiological and clinical evaluation was 59% (68% for Group A and 49% for Group B). 12 of 14 patients with p53-positive tumours and 31 of 59 with p53-negative tumours responded (P = 0.04). 6 of 7 patients with elevated c-erbB-2 had a response compared with 37 of 66 patients in the group with c-erbB-2 negative tumours (P = 0.03). Mib1 expression decreased substantially (> or = 50%) in 25 patients during treatment, of whom 20 responded compared with 21 of 48 patients with a lower decrease (P = 0.04). Response was observed in 28 of 37 patients with high baseline Mib1 (> 20%) and in 15 of 36 patients in the low Mib1 group (P = 0.05). Finally, 32 of 44 tumours with low expression of progesterone receptors responded compared with 11 of 29 tumours with high receptors expression (P = 0.05). These markers might be useful for tailoring primary and postsurgical systemic treatments.

Adult↗
PubMed1998

Pre-operative chemotherapy and radiotherapy in breast cancer.

Primary systemic treatment of breast cancer with cytotoxics yields a high response rate and allows conservative surgical procedures in bulky tumours. In order to maximise local control of disease, two innovations were introduced in a pilot study. The first was to identify the good responders after three cycles of chemotherapy and to treat them with three additional cycles. The second was to also give this group of patients a full dose of radiotherapy before surgery with the aim of verifying the rate of pathological complete remissions in view of a possible treatment of breast primary with chemoradiotherapy only. Patients were treated with doxorubicin 60 mg/m2 and cyclophosphamide, 600 mg/m2 both intravenously on day 1, every 21 days for three courses. Partial or complete responders received three more courses followed by radiotherapy (50 Gy plus a 10 Gy boost). The others underwent immediate surgery. A total of 32 patients (median age, 50 years; range 28-69 years); performance status, 0-1; T2 22, T3 8, T4 2) were enrolled and were evaluable for response and side-effects. 9 patients had only three cycles of chemotherapy due to absence of response and 23 patients had six cycles of chemotherapy. Overall, 7 patients had a complete remission, 16 a partial remission and 9 had stable disease, for an overall response rate of 72% (95% confidence interval 53-86%). In the group of patients that completed the programme, two complete pathological remissions were observed and 5 patients had only microfoci of tumour. No toxic death or grade III-IV toxicities were observed. Mild or moderate side-effects included mucositis, nausea/vomiting and leucopenia. In conclusion, our results indicate that the addition of radiotherapy to pre-operative chemotherapy did not significantly enhance the incidence of pathological complete remissions. New primary treatment approaches should be explored in this subset of patients in order to improve outcome.

Adult↗
PubMed1997

The minimal effective exemestane dose for endocrine activity in advanced breast cancer.

Phase I studies have demonstrated that exemestane, an irreversible oral aromatase inhibitor, is able to suppress circulating oestrogen levels. In our previous experience, doses ranging from 2.5 to 25 mg induced a similar suppression of oestrogens. The aim of this study was to identify the minimum effective exemestane dose on the basis of endocrine activity. 20 evaluable postmenopausal advanced breast cancer patients were randomly given exemestane 0.5, 1, 2.5 or 5 mg, in double-blind conditions. Oestrone (E1), oestradiol (E2), oestrone sulphate (E1S), gonadotrophins, sex-hormone binding globulin and dehydroepiandrosterone sulphate serum levels were evaluated from the first day of treatment to the 7th, 14th, 28th and 56th day. Serum E1, E2 and E1S levels were suppressed by all doses starting from day 7; the degree of inhibition versus baseline was 25 up to 72% for E1, 30 up to 62% for E2 and 16 up to 52% for E1S, with higher doses achieving greater suppression; these changes were maintained over time. A significant increase in FSH and LH levels was observed for all doses. Treatment tolerability was satisfactory. The endocrine effects of exemestane appear to be dose related and 0.5 and 1 mg are ineffective for adequately suppressing circulating oestrogens.

Aged↗
PubMed1997

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.

Adult↗
PubMed1997

Serum markers of bone metastases in postmenopausal breast cancer patients treated with formestane.

Bone metabolism marker evaluation is expected to play an auxiliary role in the diagnosis and follow-up of bone metastases in patients affected by different types of neoplasms. In this study we have evaluated osteoblastic and osteoclastic markers in 18 patients with bone metastases from breast cancer at diagnosis and for 1 year of follow-up during treatment with the aromatase inhibitor formestane. Osteoblastic markers include the carboxy-terminal propeptide of type I procollagen, the bone-specific alkaline phosphatase and the bone GLA protein. The carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) was evaluated as a marker of osteoclastic activity. The patients were classified into three groups according to clinical response. A good correlation between marker level modifications and clinical evolution of skeletal metastases was observed for all the examined markers. Patients with progressive disease showed increasing levels of all markers, whereas patients in regression showed a reduction compared to the basal levels; patients with stable disease fell in between these two categories. We also found that basal ICTP values have prognostic significance: in the stable and progressive disease group they were higher than in the partial response group.

Alkaline Phosphatase↗
PubMed1995

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.

17-Hydroxycorticosteroids↗
PubMed1995

Endocrinological and clinical evaluation of exemestane, a new steroidal aromatase inhibitor.

The androstenedione derivative, exemestane (FCE 24304), is a new orally active irreversible aromatase inhibitor. Fifty-six post-menopausal advanced breast cancer patients entered this study to evaluate the activity of four low exemestane doses in reducing oestrogen levels. The drug's tolerability and clinical efficacy were also assessed. Exemestane was orally administered to four consecutive groups at daily doses of 25, 12.5, 5 and 2.5 mg, and the changes in oestrogen, gonadotrophins, sex-hormone binding globulin and dehydroepiandrosterone sulphate levels were evaluated. Drug selectivity was studied by measuring 17-hydroxycorticosteroid urinary levels. After 7 days of treatment, mean oestrone and oestradiol levels had decreased by respectively 64% and 65% (a decrease which was maintained over time); in the 2.5 mg group, oestrone sulphate levels also decreased by 74%. Gonadotrophin levels were significantly higher, whereas no changes in the other serum hormone levels or any interference with adrenal synthesis were detected. Treatment tolerability was satisfactory: nausea and dyspepsia were reported in 16% of patients. The overall objective response rate was 18%. In conclusion, exemestane is effective in reducing oestrogen levels at all of the tested doses and shows interesting clinical activity.

Adult↗
PubMed1994

Formestane as treatment of advanced breast cancer in elderly women.

AIMS AND BACKGROUND: The number of elderly people is increasing, and the proportion of breast cancer in female cancer patients older than 65 years is 26%. In elderly patients, hormone therapy is widely accepted as the treatment of choice, because of its efficacy and good tolerability compared to chemotherapy. The aim of this study was to evaluate the endocrinologic and clinical activity of formestane (4-hydroxyandrostenedione), a selective aromatase inhibitor, in elderly patients with advanced breast cancer. METHODS: Thirty-five patients older than 65 years, selected from a larger group, were given formestane (250 mg or 500 mg i.m. fortnightly). Patients were evaluable for tumor response after 4 doses of formestane. Blood samples were collected to evaluate E2, FSH, LH, SHBG and DHEAS serum levels at baseline and after 2, 4, 8, 12 and 24 weeks. RESULTS: Thirty patients had PS < or = 1 (ECOG) and only 5 patients had PS = 2. Twenty-six patients were ER positive. Previous hormonal treatment for metastatic disease had been given to 17 patients; only 1 case had received chemotherapy. The overall response rate was 51% (95% C.I. 35-67%) and the median response duration was 9.5 months. Three complete responses were observed on viscera. The best responses were obtained on soft tissues (59%); on bone and viscera the response was respectively 45% and 47%. Local and systemic tolerability was highly satisfactory. Formestane induced prolonged suppression of E2 levels in all of the patients, and a significant reduction in SHBG levels was also observed from month 2 onward. A statistically significant (P = 0.0001) rise in serum FSH was also observed during the therapy. CONCLUSIONS: The study showed that formestane induced a long-lasting suppression of E2 levels and a satisfactory overall response. In our opinion, the drug is an effective and well-tolerated approach in the management of advanced breast cancer in elderly patients.

Aged↗
PubMed1994

Effect of two-4-hydroxyandrostenedione doses on serum insulin-like growth factor I levels in advanced breast cancer.

A number of endocrine treatments for advanced breast cancer seem to affect serum insulin-like growth factor I (IGF-I). The aim of our study was to investigate IGF-I levels in 33 postmenopausal patients with metastatic disease receiving the selective aromatase inhibitor 4-hydroxyandrostenedione: 250 mg (16 patients) or 500 mg (17 patients) i.m. fortnightly. Blood samples were collected before, and at one month and 3 months after the beginning of treatment for radioimmunoassay determinations. The median patient age was 56 and 60 years in the 250 and 500 mg groups respectively. Most patients had a disease free interval > or = 2 years and were oestrogen receptor positive. Objective responses were obtained in 3 patients (complete response, 1) in the 250 mg group, and in 7 patients (complete response, 3) in the 500 mg group. No significant IGF-I variations were seen in the 250 mg group, whereas a significant increase after 3 months (181.57 +/- 84.78 ng/ml versus 272.47 +/- 213.22 ng/ml, p = 0.0032) was observed in the 500 mg group. No IGF-I variations were seen between responsive and unresponsive patients in either treatment group. Our results in the 500 mg group are close to those obtained with aminoglutethimide and seem to agree with the hypothesis of an oestrogen-induced suppression of IGF-I circulating levels.

Aged↗
PubMed1994

Endocrinological and clinical evaluation of two doses of formestane in advanced breast cancer.

Formestane is a selective inhibitor of oestrogen synthesis by aromatase enzymes and induces disease regression in breast cancer patients. This phase II randomised study was carried out to determine whether there were any differences in the effects of two different doses of formestane on oestradiol (E2) serum levels and to evaluate the corresponding clinical activity in post-menopausal patients with positive or unknown oestrogen receptor status pretreated or not for advanced disease. Furthermore, possible drug interference with adrenal steroidogenesis was assessed by measuring 17-hydroxycorticosteroid (17-OHCS) urinary levels. A total of 143 patients entered the study and were randomly assigned to receive formestane 250 mg (72 patients) or formestane 500 mg (71 patients), both given i.m. every 2 weeks. In comparison with baseline, E2 serum levels decreased by an average of 40% after only 15 days and remained unchanged thereafter, with no difference being observed between the two doses. The values of 17-OHCS remained unchanged during treatment in both groups. Objective responses were 28% (19/69) in the 250 mg and 46% (31/68) in the 500 mg group. In conclusion, the two formestane doses were equally effective in reducing E2 levels without affecting adrenal function, and in inducing a considerable percentage of clinical responses.

17-Hydroxycorticosteroids↗
PubMed1994

Formestane: effective therapy in postmenopausal women with advanced breast cancer.

Aromatase inhibitors are a useful therapeutic option in the management of endocrine-dependent advanced breast cancer. Formestane (Lentaron) is the first irreversible aromatase inhibitor to be extensively investigated. In a phase II study to determine the effects of formestane on serum estradiol and urinary 17-hydroxycorticosteroid (17-OHCS) levels and to evaluate its clinical activity, 72 postmenopausal patients with advanced breast cancer were given formestane 250 mg intramuscularly every 2 weeks. Of 66 patients fully evaluable, 56 were estrogen receptor (ER) positive, and 43 had a disease-free interval > or = 2 years. Metastases were assessable in soft tissue (53%), bone (53%) and viscera (47%); 34 patients had 1, 32 had > or = 2 metastatic lesions. Serum estradiol levels fell significantly (p < 0.01) after 2 weeks and remained unchanged thereafter, whereas urinary 17-OHCS levels did not change during treatment. Objective responses were obtained in 19 patients (29%), of whom 8 had complete response. In relation to disease sites, similar responses were obtained in soft tissue (33%) and viscera (30%), whereas response in bone was 18%. The overall tolerability of formestane was satisfactory, and only two patients complained of local side effects. We conclude that formestane is an effective aromatase inhibitor in postmenopausal patients with hormone-dependent breast cancer, and does not interfere with adrenal steroidogenesis.

17-Hydroxycorticosteroids↗
PubMed1993

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.

Aged↗
PubMedDate not supplied

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.

Aged↗