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Biomedical subjects

D Crivellari

Publications and source records attributed to D Crivellari.

At least 37 records · Page 2Linked to original sources

Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII.

PURPOSE: Information on the tolerability and efficacy of adjuvant chemoendocrine therapy for older women is limited. We studied these issues using the data collected as part of the International Breast Cancer Study Group Trial VII. PATIENTS AND METHODS: Postmenopausal women with operable, node-positive breast cancer were randomized to receive either tamoxifen alone for 5 years (306 patients) or tamoxifen plus three consecutive cycles of classical cyclophosphamide (100 mg/m(2) orally days 1 to 14), methotrexate (40 mg/m(2) intravenous days 1 and 8), and fluorouracil (600 mg/m(2) intravenous days 1 and 8) every 28 days (CMF; 302 patients). The median follow-up was 8.0 years. RESULTS: Among the 299 patients who received at least one dose of CMF, women 65 years of age or older (n = 76) had higher grades of toxicity compared with women less than 65 years old (n = 223) (P =.004). More women in the older age group compared with the younger women experienced grade 3 toxicity of any type (17% v 7%, respectively), grade 3 hematologic toxicity (9% v 5%, respectively), and grade 3 mucosal toxicity (4% v 1%, respectively). Older patients also received less than their expected CMF dose compared with younger postmenopausal women (P =.0008). The subjective burdens of treatment, however, were similar for younger and older patients based on quality-of-life measures (performance status, coping, physical well-being, mood, and appetite). For older patients, the 5-year disease-free survival (DFS) rates were 63% for CMF plus tamoxifen and 61% for tamoxifen alone (hazards ratio [HR], 1.00; 95% confidence interval [CI], 0.65 to 1.52; P =.99). For younger patients, the corresponding 5-year DFS rates were 61% and 53% (HR, 0.70; 95% CI, 0.53 to 0.91; P =.008), but the test for heterogeneity of CMF effect according to age group was not statistically significant. The reduced effectiveness of CMF among older women could not be attributed to dose reductions according to dose received. CONCLUSION: CMF tolerability and effectiveness were both reduced for older patients compared with younger postmenopausal node-positive breast cancer patients who received tamoxifen for 5 years. The development and evaluation of less toxic and more effective chemotherapy regimens are required for high-risk elderly patients.

Age Factors↗

Dose-finding and pharmacologic study of chronic oral idarubicin therapy in metastatic breast cancer patients.

Oral idarubicin (IDA) is an active drug in metastatic breast cancer, but its role in the management of this tumor is yet not established completely. To investigate a new modality of IDA administration, a dose-finding study was designed with hyperfractionated doses. The purpose was to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the pharmacokinetics of this schedule. IDA was administered twice daily as outpatient therapy in cycles of 3 weeks followed by a 1-week rest. Thirty-one patients with progressive metastatic breast cancer and pretreated with chemotherapy (including epirubicin and doxorubicin) were enrolled. DLT was defined as G4 hematological toxicity or any other toxicity G3 or higher (Bloom and Richardson grading). Inter- and intrapatient dose increases were studied. Pharmacokinetics of IDA and its metabolite idarubicinol (IDOL) were evaluated. IDA dose was increased from 2 mg/day to 10 mg/day, by steps of 1 mg/day, with the larger dose given in the evening. MTD was reached at 10 mg/day. Overall, the therapy cycles were 69 (median/patient, 2; range, 1-6). DLTs were G4 neutropenia associated with leukopenia and thrombocytopenia in one patient and G3 diarrhea in another of the 5 patients in the 10 mg/day cohort. The two patients developing DLT at the daily dose of 10 mg received a dose normalized for body surface of 6.85 and 5.65 mg/m2/day, respectively. We considered 5.5 mg/m2/day to be the MTD. Other toxicities were nausea, vomiting, neutropenia, and diarrhea, grades G1 to G2. By univariate analysis, significant correlations were observed between absolute neutrophil count at nadir and IDA area under the curve (P = 0.022; r = -0.33), IDA Cmax (P = 0.0067; r = -0.38), IDOL area under the curve (P = 0.0009; r = -0.43), and IDOL Cmax (P = 0.0016; r = -0.41), respectively. By multivariate analysis, IDA Cmax was the strongest determinant for neutropenia (R2 = 0.14; P = 0.01). Among the 21 patients evaluable for response, 3 (14.3%) had partial response (lasting 3, 6, and 8 months, respectively), and 6 (28.6%) had a complete arrest of disease progression (lasting 2-6 months). In conclusion, the MTD of this schedule is 10 mg/day and the DLTs are neutropenia and diarrhea. Tolerance was good, and the treatment is feasible as home therapy. Some objective measurable responses were documented in this group of anthracycline-pretreated patients. IDOL could have a role for the pharmacological effect. Further evaluation of this schedule is warranted to assess the activity and toxicity of prolonged oral IDA administration.

Administration, Oral↗

BRCA1 and BRCA2 genes: role in hereditary breast and ovarian cancer in Italy.

The heritable defects of BRCA1 and BRCA2 genes have been shown to predispose to breast and ovarian cancers. In a previous report, we analyzed 46 Italian families with breast and/or ovarian cancer for BRCA1 mutations. In the present study, those families and 11 others were screened for BRCA2 mutations; the newly enrolled families were also analyzed for the BRCA1 gene. The coding region and splice boundaries of BRCA2 and BRCA1 genes were assessed by the protein-truncation test and single-strand conformational polymorphism. A total of 20 different mutations were found in 21 families (37%). A total of 9 families (16%) showed mutations in the BRCA1 gene, including the one new mutation identified in this study (5382insC), and 12 families (21%) presented mutations in the BRCA2 gene. BRCA2-mutated families presented breast and ovarian cancers or breast cancers only, whereas most BRCA1-mutated families presented ovarian cancer alone or in association with breast cancer. All the BRCA2 mutations led to a truncated protein: 6 were frameshift mutations, 4 were non-sense mutations and 2 involved the intronic invariant region leading to splice variants. Therefore, in the Italian population, the cumulative proportion of BRCA1 and BRCA2 mutations was within the range observed in other studies (37%), with higher involvement of BRCA2 than of BRCA1. Many families in which no mutations were found presented a very high incidence of breast and/or ovarian cancer. Among the 36 BRCA1 and BRCA2 wild-type families, 24 presented at least 4 cancer cases, indicating the existence of other important predisposing genes.

Adult↗

Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer.

BACKGROUND: Anthracyclines and taxanes are the most active drugs against breast cancer and the search after their optimal combination is under intensive investigation in both the advanced and early disease settings. A dose-finding study of epidoxorubicin (E) and docetaxel (D) was conducted in advanced breast cancer (ABC) to define the maximum tolerated dose (MTD) of the combination with and without granulocyte colony-stimulating factor (G-CSF) support and to characterise its toxicity and activity profile. PATIENTS AND METHODS: Forty-two patients who received neither palliative chemotherapy nor adjuvant anthracyclines (55% with dominant visceral disease and 66% with > or = 2 sites involved) with measurable/evaluable lesions, were treated at four dose levels starting from E 75 mg/m2 and D 75 mg/m2 to E 120 mg/m2 and D 85 mg/m2. A maximum of four cycles of the combination was given every three weeks and four additional cycles of single agent D were allowed in responding patients. Cardiac function was monitored at baseline and at every second course by echocardiography. RESULTS: Febrile neutropenia (two patients) and prolonged, severe neutropenia (absolute neutrophil count (ANC) < 0.1 x 10(9)/l for more than three days; one patient) defined the MTD of the combination without G-CSF support at E 90 mg/m2 and D 75 mg/m2. G-CSF was then routinely administered from the subsequent dose level of E 120 mg/m2 and D 75 mg/m2. The MTD with G-CSF support was established at E 120 mg/m2 and D 85 mg/m2 (one patient with neutropenic fever together with failure of ANC recovery at day 21, three patients with ANC less than 0.1 x 10(9)/l for more than three days, one patient with both and one patient with grade 4 thrombocytopenia and toxic death from typhlitis while neutropenic). No severe neurotoxicity, mucositis, or fluid retention were observed and there were no clinical signs of cardiotoxicity. Antitumor activity was not a primary endpoint of the study: the overall response rate (ORR) in 40 evaluable patients was 60% (95% confidence interval: 43%-75%, 58% in liver disease, 84% in soft tissue) with no apparent dose-related effect. After a median follow-up of 19 months (range 2-30+), the overall time to progression (TTP) in nine patients without maintenance hormonal therapy was five months. CONCLUSIONS: The combination of E and D proved to be an effective and safe regimen in poor- prognosis patients with ABC. G-CSF support allowed higher doses to be delivered safely but dose escalation did not translate into improved response rates (RR). The MTD without growth factors support was used, in a phase II trial, which also included patients with previous anthracycline-containing adjuvant regimens.

Adult↗

Low incidence of BRCA1 mutations among Italian families with breast and ovarian cancer.

Most familial breast or ovarian cancers are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. The cloning of these genes has opened a new era for the genetic counseling of women with a family history of breast or ovarian cancer. To estimate the incidence of detectable BRCA1 mutations and to define the eligibility criteria for genetic testing in the Italian population, a total of 53 patients belonging to 46 families clustering multiple cases of breast and/or ovarian cancer were investigated. Seven families presented with ovarian cancer only, 16 had both ovarian and breast cancers, and 23 were characterized by breast cancer only. Using a combination of protein truncation test (PTT) and single strand conformational polymorphism (SSCP) analysis followed, when necessary, by direct sequencing, we found 8 distinct mutations, 2 of these not reported before. Five frameshift and 2 nonsense mutations led to a truncated protein. One mutation was a missense substitution involving a cysteine in the zinc finger domain. One variant creating an ETS binding site in intron I was found but its role was not defined. The percentage of families carrying mutations was 17%. Among the families characterized by ovarian cancer only and by breast and ovarian cancer, the percentage of BRCA1 mutations was 57% and 12.5%, respectively. In contrast, the percentage of altered BRCA1 in families with only breast cancers was 9%. In the 46 Italian families studied, BRCA1 mutations were detected in fewer kindreds than those previously hypothesized based on linkage analysis, especially when these were characterized by breast cancers only. Our results indicate that families with a low number of cancer patients should be referred for BRCA1 genetic testing mainly when ovarian cancer is present.

Adult↗

Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) Trial VI.

Adjuvant chemotherapy-induced amenorrhoea has been shown to be associated with reduced relapses and improved survival for premenopausal breast cancer patients. Amenorrhoea was, therefore, studied to define features of chemotherapy (i.e. duration and timing) and disease-related factors which are associated with its treatment effects. We reviewed data from IBCSG Trial VI, in which accrual was between July 1986 and April 1993. 1196 of the 1475 eligible patients (81%) were evaluable for this analysis. The median follow-up was 60 months. Women who experienced amenorrhoea had a significantly better disease-free survival (DFS) than those who did not (P = 0.0004), although the magnitude of the effect was reduced when adjusted for other prognostic factors (P = 0.09). The largest treatment effect associated with amenorrhoea was seen in patients assigned to receive only three initial CMF courses (5-yr DFS: 67% versus 49%, no amenorrhoea; hazard ratio, 0.55; 95% confidence interval, 0.38 to 0.81; P = 0.002). DFS differences between amenorrhoea categories were larger for patients with ER/PR positive tumours (hazard ratio, 0.65; 95% confidence interval, 0.53 to 0.80; P = 0.0001). Furthermore, patients whose menses returned after brief amenorrhoea had a DFS similar to those whose menses ceased and did not recover (hazard ratio, 1.10; 95% confidence interval, 0.75 to 1.62; P = 0.63). The effects associated with a permanent or temporary chemotherapy-induced amenorrhoea are especially significant for node-positive breast cancer patients who receive a suboptimal duration of CMF chemotherapy. Cessation of menses, even for a limited time period after diagnosis of breast cancer, might be beneficial and should be prospectively investigated, especially in patients with oestrogen receptor-positive primaries.

Adult↗

Pharmacokinetics and tolerance of vinorelbine in elderly patients with metastatic breast cancer.

25 patients older than 65 years with metastatic breast cancer were treated with vinorelbine 30 mg/m2 i.v. days 1 and 8 every 3 weeks; the pharmacokinetics were studied in 10 of them. Vinorelbine showed a large apparent volume of distribution (mean 23.4 l/kg), a long terminal half-life (mean 26.2 h) and a large systemic clearance rate (mean 1.2 l/kg). These results are similar to those reported in younger patients. No correlation has been found between toxicity, age and drug exposure. We observed 6 partial responses out of 20 evaluable patients despite a relatively low mean dose intensity (67%). Severe neutropenia occurred in 37% of the patients; other side-effects were acceptable. This study does not provide a pharmacokinetic rationale for reducing the dosage of vinorelbine in selected elderly patients.

Age Factors↗

Menstrual cycle and timing of breast surgery in premenopausal node-positive breast cancer: results of the International Breast Cancer Study Group (IBCSG) Trial VI.

PURPOSE: It has been postulated that breast cancer surgery performed during the follicular phase of the menstrual cycle is associated with poorer outcome. PATIENTS AND METHODS: We tested this hypothesis by evaluating disease-free survival (DFS) for 1033 premenopausal patients who received definitive surgery either during the follicular phase (n = 358) or the luteal phase (n = 675). All patients were enrolled in a randomized trial conducted between July 1986 and April 1993. All had node positive breast cancer and randomization was stratified by estrogen receptor (ER) status. All patients received at least three cycles of adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). The median follow-up was 60 months. RESULTS: Patients who underwent definitive surgery for breast cancer in the follicular phase had a slightly worse disease-free survival than those operated on during the luteal phase (five-year DFS percentage: 53% versus 58%; hazard ratio, 1.13; 95% confidence interval (CI), 0.94-1.38; P = 0.20). The effect was significantly greater for the subpopulation of 300 patients with ER-negative primaries (P = 0.02 interaction effect; five-year DFS percentages 42% vs. 59%; hazard ratio 1.60; 95% CI, 1.12-2.25; P = 0.008). The effect of timing of surgery diminished for analyses based on lesser surgical procedures, e.g., excisional biopsies. In particular, no effect of timing was observed for fine needle aspiration procedures. CONCLUSIONS: Surgical procedures which are more extensive than a fine needle aspiration biopsy might be associated with worse prognosis if conducted during the follicular phase of the menstrual cycle. This phenomenon was seen predominantly for high risk breast cancer with low levels or no estrogen receptors in the primary tumor.

Breast Neoplasms↗

Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. International Breast Cancer Study Group.

BACKGROUND: Adjuvant therapy for early breast cancer is effective but may be toxic. Our aim was to investigate the impact of the presence, timing, and duration of adjuvant chemotherapy on patients' perceptions of their quality of life (QL). METHODS: International Breast Cancer Study Group trial VI assessed adjuvant chemotherapy in 1475 premenopausal and perimenopausal patients, and trial VII assessed adjuvant tamoxifen or chemoendocrine therapy in 1212 postmenopausal patients with node-positive breast cancer. Patients were asked to complete a QL questionnaire-single-item linear analogue self-assessment scales measured physical wellbeing, mood, appetite, and perceived adjustment/coping. QL was assessed in this way at the beginning of treatment, 2 months after the start of treatment, every 3 months, and at 1 and 6 months after recurrence. FINDINGS: Baseline QL scores decreased as the number of involved axillary nodes increased (for example, mean mood score: 66.1 for women with one positive node, 66.4 for two to four positive nodes, 61.3 for five to nine positive nodes, and 59.1 for ten or more positive nodes; p = 0.008 for trends), and were lower in patients with oestrogen-receptor-negative than in patients with oestrogen-receptor-positive tumours (61.4 vs 66.3, p = 0.0009). All treatment groups showed substantial improvement in QL scores during adjuvant therapy. Patterns of QL scores reflected presence, duration, and timing of cytotoxic treatment. Longer initial cytotoxic therapy delayed improvement in QL scores. Later cytotoxic therapy had transient adverse effects. Anticipation of future therapy also affected QL scores. INTERPRETATION: Overall, chemotherapy had a measurable adverse effect on QL, but this effect was transient and minor compared with patients' adaptation/coping after diagnosis and surgery. This finding should encourage patients and doctors to choose appropriate adjuvant therapy with less concern for initial toxicity.

Antineoplastic Agents, Hormonal↗

Vinorelbine treatment of advanced non-small cell lung cancer with special emphasis on elderly patients.

The aim of this study was to investigate the activity and the toxicity of vinorelbine (VNB) in a population of patients with locally advanced inoperable or metastatic non-small cell lung cancer (NSCLC) including elderly patients unfit for cisplatin-based chemotherapy. VNB was administered at a dose of 25-30 mg/m2, intravenously, weekly until progression. Of the 83 patients who entered the study (median age 63 years, number of patients aged > or = 70 years = 23, median performance status = 80, stage IV in 58 patients, previous chemotherapy in 15 patients), 76 were evaluable. One complete remission and 22 partial remissions were noted (30.2% response rate). Toxicity was mild. Median survival was 9 months. No effect of age upon outcome was detected. Thus, single agent VNB is a reasonable option for advanced NSCLC, particularly in elderly patients.

Adult↗

Routine tests during follow-up of patients after primary treatment for operable breast cancer. International (Ludwig) Breast Cancer Study Group (IBCSG)

BACKGROUND: Follow-up tests for patients after diagnosis and primary treatment of breast cancer are routinely performed. However, the usefulness of these follow-up parameters remains unclear. We determined the yield of a variety of blood tests used to detect the presence of overt metastatic disease. METHODS: 4105 patients enrolled in International (Ludwig) Breast Cancer Study Group (IBCSG) randomized clinical trials from 1978 to 1985 were analyzed for abnormal or equivocal findings in six routine blood tests obtained every 3 months for the first two years, every six months for years 3-5 and yearly thereafter. The relationship of test results to the occurrence of overt metastatic disease was evaluated. The relapses were categorized as follows in order to estimate the yield of the different tests for relevant sites of metastases: any breast cancer relapse, bone +/- other; liver +/- other. RESULTS: Alkaline phosphatase alone was abnormal in a high proportion of patients with either bone metastases, liver metastases, or both. SGOT and gamma-GT were also sensitive for patients with liver metastases. Bilirubin, serum calcium, and serum creatinine were relatively insensitive indicators of relapse. Abnormal test results were reported sometime during a patient's disease-free period for 3% to 6% of patients, depending on the test. CONCLUSIONS: Alkaline phosphatase was the most effective blood test to distinguish patients with relapse from those without relapse. It is inexpensive and its yield is relatively high for predicting liver and bone metastases. The routine use of the other tests analyzed to detect metastases was not justified.

Breast Neoplasms↗

Cisplatin and etoposide versus cyclophosphamide, epirubicin and vincristine in small cell lung cancer: a randomised study.

From September 1986 until December 1991, 139 patients with histologically-proven small cell lung cancer, age < 75 years, performance status > 40, absence of brain metastases and no previous treatment, were randomised to receive either CEV cyclophosphamide 1000 mg/m2 intravenous (i.v.), epirubicin 70 mg/m2 i.v., vincristine 1.2 mg/m2 i.v., every 3 weeks or PE (cisplatin 20 mg/m2 i.v. and etoposide 75 mg/m2 i.v. for 5 consecutive days, every 3 weeks) for six cycles. After three cycles, responding patients received radiotherapy to the chest (45 Gy/15 sessions) and to the brain (30 Gy/10 sessions--only in patients with limited disease achieving complete remission). 3 patients were ineligible. Patient characteristics included (CEV/PE) total number 66/70, median age 60/61 years, median performance status 80/80, extended disease 33/48 cases (P = 0.04). In evaluable patients, 42/62 (67.7%) responded to CEV while 42/58 (72.4%) responded to PE (P = non-significant); respective complete response rates were 16.1 and 29.3% (P = non-significant) and respective complete response rates in patients with extended disease were 9.4 and 28.9% (P = 0.03). Median survival was 10.5 months, without significant differences in the two treatment arms, even after adjustment for stage. PE was less well tolerated than CEV. Although PE is more active than CEV in certain subsets of patients, its apparent inability to improve survival in this and in other studies questions its routine use in small cell lung cancer.

Adult↗

Epirubicin and ifosfamide in advanced soft tissue sarcomas.

BACKGROUND: To evaluate the feasibility, toxicity and efficacy of the combination of (IFO) ifosfamide and epirubicin (EPI) given at conventional doses for monochemotherapy, we started a phase II study in advanced/metastatic soft tissue sarcoma patients. PATIENTS AND METHODS: Treatment consisted of: epirubicin 75 mg/m2 i.v. day 1; IFO 1.8 g/m2 days 1 to 5; MESNA 20% of the IFO dose at 4-hour intervals three times a day during IFO administration. Cycles were given every 3-4 weeks for at least three cycles. RESULTS: The overall response rate for non-visceral sarcomas (51 pts) was 31% (95% confidence limits +/- 13%). Among the 13 visceral sarcomas no response was seen for the leiomyosarcomas of the gastrointestinal tract, whereas one complete and one partial remission were observed for the uterine sarcomas. The duration of response was 10 months (range 5-34+) for complete responses and 9 (range 4-42+) for partial responses. The median survival for responders is 18 months (range 2-60+) and for non-responders 10 months (range 1-33) (p < 0.004). CONCLUSIONS: This combination proved to be feasible and tolerable. The overall response rate does not appear to be superior to those with other standard treatments, but it should be pointed out that our patient population was totally unselected.

Adolescent↗

[Evaluation of the specific delayed cutaneous hypersensitivity response(DTCH) after specific active immunotherapy (SAI) using autologous tumor cells in patients operated upon for renal carcinoma].

From Dec 1986 to Dec 1990, 113 consecutive patients radically resected for renal cell carcinoma, have been randomized after surgery to observation or to Active Specific Immunotherapy (A.S.I.). 43 patients stage I-II and 13 p. stage III, according to TNM entered the treatment arm consisting of 10 autologous irradiated tumor cells injected intradermally, either mixed with BCG 10(7) (on days 28th and 35th after surgery) or alone (on day 42th). At randomization and 1, 6 and 12 months after treatment, patients were evaluated for the development of a DTCH to autologous tumor and to autologous normal cells, obtained by mechanical and enzymatic dissociation of the surgical specimens. Baseline DTCH were negative in all patients. One month after completing A.S.I. 36 out of 50 evaluable patients displayed a significant DTCH response to autologous tumor, which remained positive in 23/40 patients at 6 months. Our data clearly indicate that Active Specific Immunotherapy with autologous tumor cells mixed with BCG can elicit a specific immune response to autochthonous tumor as measured by DTCH.

Adult↗

Biochemical markers for detecting bone metastases in patients with breast cancer.

A study was carried out to assess the best use of biochemical bone markers to exclude metastases in patients with breast cancer. Urinary galactosyl-hydroxylysine and serum alkaline phosphatase were used to monitor bone resorption and deposition, respectively. Hydroxyproline was also measured. In a selected population of patients, possibly affected by metastases on the basis of scintigraphic examination, which is highly sensitive but poorly specific, we assessed the efficiency of the markers by a double statistical analysis. In this group, the only marker able to predict metastases was galactosyl-hydroxylysine.

Alkaline Phosphatase↗

Adjuvant therapy for primary breast cancer in a female patient affected by autoimmune liver disease: does it cure breast cancer and primary biliary cirrhosis?

Polychemotherapy (CMF or CMF-like regimens) is the treatment of choice in premenopausal breast cancer patients with 1-3 positive nodes. In clinical practice, patients with abnormal biochemical tests of liver function are usually excluded from this potentially curative methotrexate-containing regimen in order to avoid worsening of hepatic damage. On the other hand, recent reports have shown a beneficial effect of methotrexate in a particular autoimmune liver disease such as primary biliary cirrhosis. We discuss the case of a female patient with breast cancer and primary biliary cirrhosis whose biochemical tests of liver function and the titer of antimitochondrial antibody persistently improved after treatment with 3 cycles of CMF. In conclusion, we suggest that the CMF regimen is potentially useful in patients with breast cancer and primary biliary cirrhosis.

Antineoplastic Combined Chemotherapy Protocols↗