[Medical indoor environment counsellor (MIEC) in Burgundy: evaluation by physicians and patients]. / Activité du conseil médical en environnement intérieur (CMEI) en Bourgogne : évaluation auprès des médecins et des patients.

UNLABELLED: Since December 2009, chest physicians and allergologists in Burgundy have been able to call upon a medical indoor environment counsellor (MIEC). The consultations are free for the patient and are undertaken following a medical referal after systematic cutaneous prick tests. AIMS: To describe the indications, the distribution of prescriptions and to measure the impact of the counsellor's visits on the first 100 patients at 6 months and on the physicians at 18 months. METHOD: Telephone interviews with the 67 physicians (whether prescribers or not) concerning their motivation and/or expectations, and with the first 100 patients concerning follow up of the recommendations. RESULTS: Seventy percent of the physicians replied (n=47). The satisfaction of prescribers (n=22) was 8.42/10. The indications were rhinitis and a poorly controlled asthma. The requests concerned the search for dust mite (50%) and moulds (46%). Eighty-four percent of the physicians discussed the MIEC's report with the patients. The patients' symptoms were rhinitis (79%), asthma (57%) and conjunctivitis (33%). The Acarex test(®), performed in cases of positive prick tests to house dust mites (n=72), was strongly positive for 67 patients. Sixteen mould samples out of 21 were above the standard concentrations. Sixty-nine patients had followed the recommendations of the MIEC. CONCLUSION: The impact of the MIEC visits was perceived as positive by the physicians and the patients. The medico-economic impact warrants further evaluation.

Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer.

BACKGROUND: The purpose of this study was to evaluate the impact of a dose-dense primary chemotherapy on pathological response rate (pCR) in patients with locally advanced breast cancer (LABC) treated with combined modality therapy. PATIENTS AND METHODS: Stage IIIA/IIIB patients received three courses of induction chemotherapy (ICT) with cyclophosphamide, epirubicin and 5-fluorouracil (CEF) followed by local therapy (total mastectomy or segmental mastectomy with axillary nodes dissection) and adjuvant chemotherapy (ACT) with three courses of CEF alternated with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Patients were randomized to receive ICT and ACT every 3 weeks (arm A, 'standard treatment') or every 2 weeks with granulocyte-macrophage colony-stimulating factor (GM-CSF) support (arm B, 'dose-dense treatment'). In both arms radiotherapy was administered after the end of chemotherapy (in selected cases) and patients with hormonal receptor-positive tumors received tamoxifen for 5 years. RESULTS: A total of 150 patients were randomized (77 arm A and 73 arm B) and demographics were well balanced between the two arms. Compliance to treatment was excellent: 95% and 93% of patients in arms A and B, respectively, completed the treatment program with no modification or delay. Median duration of treatment (ICT+local+ACT) was 183 days (range 0-265) in arm A and 139 days (0-226) in arm B. The average relative dose intensity (ARDI) of chemotherapy was 1.3 with a 30% increase in the dose intensity in arm B in comparison with arm A. No difference in clinical [62%; 95% confidence interval (CI) 49% to 73.2%] and pathological response rates to ICT was observed between the two arms. Median follow-up was 5 years (range 1-96 months); median disease-free survivals were 4.8 years in arm A and 4.5 years in arm B. Median overall survival was 7.8 years in standard therapy: this figure has not yet been reached in the dose-dense treatment. CONCLUSIONS: In LABC a dose-dense regimen, while allowing a 30% increase in the dose intensity of chemotherapy, did not provide significant improvement in pathological response rates. However, accelerated chemotherapy reduced the duration of the combined-modality program (6.1 versus 4.6 months) with no additional toxicities.

Thymidine labeling index analysis in early breast cancer patients randomized to receive perioperative chemotherapy.

OBJECTIVE: To identify through a substudy of a larger, multicenter study of adjuvant treatment in primary operable breast cancer patients any possible correlation between cellular proliferation rate, measured by thymidine labeling index (TLI), and perioperative chemotherapy (periCT). METHODS: TLI was measured in slices of early breast carcinoma patients. The main trial was designed to randomize patients after primary surgery to receive one cycle of periCT consisting of cyclophosphamide, epidoxorubicin and 5-fluorouracil, or no periCT. RESULTS: Of 600 patients randomized into the main study, 197 were eligible for inclusion in this substudy. Characteristics of patients were quite similar to those of the entire population entered into the main study. The TLI cutoff value in our series was 0.7% expressed as the median percentage ratio of thymidine-labeled cells undergoing DNA synthesis in the tumor cell population of specimens from the 197 patients. No differences were observed in terms of relapse-free survival (RFS) and overall survival (OS) after grouping the patients by TLI value (low and high) and by treatment. Among node-negative patients, a significant improvement in terms of OS (p = 0.02), but not RFS (p = 0.06), was seen in patients with a high-TLI value who underwent periCT versus controls. CONCLUSIONS: TLI may be a useful tool for the identification of node-negative patients with high-TLI values who may benefit from periCT.

Metastatic breast cancer patients failing first-line, anthracycline-containing chemotherapy: is further therapy of benefit?

During the last 50 years median survival for metastatic breast cancer has not varied and remains 2-3.5 years. To assess the clinical benefit of salvage systemic therapy a retrospective analysis of metastatic breast cancer patients all homogeneously treated with a commonly used first-line anthacycline-containing cytotoxic regimen (FEC) was undertaken. The 140 patients in this report were among 375 entered in two consecutive multicenter randomized trials carried out from Dec. 1983 to Jan. 1990. All patients died during follow-up. Median number of salvage therapies was 3 (range 1-7). Response rate (CR and PR) was 41% with FEC and 7%, 3%, 15%, 0%, 14%, 0%, 0% in patients receiving salvage treatment line 1 to 7, respectively. Time to treatment failure (TTF) was 7.5 months for FEC and 3.5, 2.5, 2.1, 1.6, 2.1, 1.1, 1.6 months at first to seventh salvage treatment, respectively. Only a very small fraction of patients receiving first-line FEC respond to subsequent palliative treatment. The advantages of salvage therapy are unclear and must be weighed against the inconvenience, cost and morbidity of treatment. After first salvage therapy, patients should be considered for randomized trials comparing systemic antineoplastic therapy with best palliative care. Endpoints of all future clinical trials in metastatic breast cancer should include measurement of quality of life and accurate, sequential measurement of symptom control.

Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.

PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

Primary chemotherapy in locally advanced breast cancer (LABC): effects on tumour proliferative activity, bcl-2 expression and the relationship between tumour regression and biological markers.

The rate of tumour cell proliferation evaluated by the [3H]-thymidine labelling index ([3H]-dT-LI) is known to be an independent prognostic factor in patients with operable breast cancer and significantly predicts the response to chemotherapy in patients with advanced disease. In locally advanced breast cancer (LABG), we examined whether chemotherapy induced modifications in [3H]-dt-LI, and bcl-2 expression and their relationship with tumour regression and prognosis. 70 LABC patients received three courses of primary chemotherapy (FEC: 5-fluorouracil 600 mg/m2, epidoxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2, followed by surgery and subsequent adjuvant chemotherapy consisting of three courses of FEC alternated with three courses of CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2). Tumour biological markers were evaluated on diagnostic biopsy, before primary chemotherapy and at surgery. Tumour cell proliferation was determined by [3H]-dT-LI, whilst bcl-2 expression was examined by immunohistochemical staining. The overall response rate to primary FEC was 74.3% (95% confidence interval 57.6-83.2%). The response rate correlated with high [3H]-dT-LI: 88% (29/33) of patients with high [3H]-dT-LI achieved an objective response compared with 62% (23/37) of patients with low [3H]-dT-LI (P = 0.014). The 3 patients achieving a pathological complete response after induction treatment had high proliferative tumours. The highest 2-year relapse free survival (66.6%) was observed in patients with low [3H]-dT-LI after primary chemotherapy. The median bcl-2 expression values before and after primary chemotherapy were 0% (range 0-80) and 30% (range 0-90), respectively (P = 0.03). Our data indicate that primary chemotherapy can modulate tumour cell kinetics and apoptosis-related genes. Pretreatment proliferative activity correlated with tumour response, whilst post-treatment [3H]-dT-LI correlated with relapse free survival.

Vinorelbine as palliative therapy in advanced breast cancer.

Thirty advanced breast cancer patients received Vinorelbine (VNB) according to two different schedules: a weekly i.v. bolus of 30 mg/m (14 patients) or a continuous infusion (CI) schedule comprising 8 mg i.v. bolus on day 1 followed by 8 mg/m2/die CI day 1 to 4, q 21 days (16 patients). 36% of patients had received at least two prior chemotherapy regimens for advanced disease and 57% had been treated with anthracycline-based palliative therapy. The overall response rate (CR + PR) was 33% (soft tissue 57%, bone 17%, viscera 29%). The main toxicities were neutropenia and abdominal pain. Vinorelbine is effective in pretreated advanced breast cancer patients.

A randomized trial of chemotherapy with or without estrogenic recruitment in locally advanced breast cancer. North-West Oncology Group (GONO) Study, Italy.

The present phase III trial was carried out to verify whether a kinetic recruitment induced by low doses of diethylstilbestrol (DES) could increase the killing efficacy of chemotherapy in patients with locally advanced breast cancer. One-hundred and seventeen untreated patients with locally advanced breast cancer (stage IIIA/IIIB) were randomized to receive 3 courses of primary chemotherapy consisting of cyclophosphamide (600 mg/m2 i.v.), doxorubicin (50 mg/m2 i.v.) and fluorouracil (600 mg/m2 i.v.) (CAF) on day 1, or DES-CAF (DES, 1 mg orally days 1-3, CAF on day 4). The courses were repeated every 3 weeks. The patients who achieved an objective response were submitted to mastectomy followed by 3 courses of CAF alternated with 3 courses of CMF (cyclophosphamide, 600 mg/m2 i.v.; methotrexate, 40 mg/m2 i.v.; fluorouracil, 600 mg/m2 i.v.), with or without DES. The two treatment arms were well balanced in terms of clinical and pathologic features. There was no significant difference in response rates to induction chemotherapy between the two treatment arms (objective response rate, 63.3% for CAF and 56.1% for DES-CAF). Median overall survival was 49 and 47 months and median progression-free survival was 24 and 21 months for CAF and DES-CAF patients, respectively. Toxicity was not significantly different in the two groups, with the exception of leukopenia: DES chemotherapy was significantly more myelotoxic than the standard treatment, which resulted in a significant reduction in the actual dose intensity. In spite of the attractive experimental evidence, we conclude that so far there is no clinical advantage in the combination of estrogen and chemotherapy. Further research is needed to investigate different schedules of chemotherapy and hormones, or to test the possibility of combining various mitogens.

Chemotherapy with or without estrogenic recruitment in metastatic breast cancer. A randomized trial of the Gruppo Oncologico Nord Ovest (GONO).

BACKGROUND: This phase III study was carried out to verify whether a kinetic recruitment induced with low doses of diethylstilbestrol (DES) could increase the antitumor activity of chemotherapy in patients with advanced breast cancer. PATIENTS AND METHODS: Two hundred fifty-eight women with metastatic breast cancer were randomized to receive chemotherapy consisting of cyclophosphamide 600 mg/sqm i.v., epidoxorubicin 60 mg/sqm i.v. and fluorouracil 600 mg/ sqm i.v. (CEF) on day 1 or DES-CEF (diethylstilbestrol 1 mg orally days 1-3 CEF on day 4) every 21 days. Patients were treated until progression or, if responsive, for a maximum of 10 courses. RESULTS: There were no significant differences between the two treatment arms in response rates (51.3% to CEF and 49.6% for DES-CEF); median progression-free survival (9.4 months for CEF and 11 months for DES-CEF group) or median overall survival (17.3 and 20 months for CEF and DES-CEF arms, respectively). Non-hematological toxicities were superimposable in the two arms, while DES-chemotherapy was more myelotoxic. CONCLUSIONS: This trial confirms that chemotherapy preceded by estrogenic recruitment is still in an experimental phase and that, at present, it has no role in clinical practice. Further research is needed to test the possibility of combining different mitogens in the light of new information about breast cancer cell growth.

Locally advanced non-metastatic breast cancer: analysis of prognostic factors in 125 patients homogeneously treated with a combined modality approach.

125 stage III breast cancer patients, including 51 cases of inflammatory carcinoma, were treated with the following combined modality approach: three courses of primary 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) chemotherapy followed by locoregional treatment and subsequent adjuvant chemotherapy consisting of three courses of FAC alternating with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Clinical response to primary FAC was 65% (complete 10%). Residual tumour mass in the mastectomy specimen was > 1 and < or = 1 cm in 82 and 18% of cases, respectively. Complete pathological response following primary chemotherapy was achieved in only 3.5% of cases. After primary FAC and local treatment, 97% of patients were disease-free. Overall survival (S) and progression-free survival (PFS) at 5 years were 56 and 34%, respectively. Univariate analysis showed that age, receptor status and clinical and pathological response to primary chemotherapy did not appear to influence treatment outcome significantly, whereas stage, presence of inflammatory disease and number of involved nodes had a significant impact on both S and PFS.

In vivo cytokinetic effects of recombinant human growth hormone (rhGH) in patients with advanced breast carcinoma.

We have investigated the possibility of inducing a kinetic recruitment of breast cancer cells by the in vivo administration of recombinant human Growth Hormone (rhGH). Twelve patients with advanced breast cancer received rhGH i.m. for 2 days immediately before the first course of chemotherapy. The following biological parameters have been evaluated before and 24 hours after rhGH administration: tumor TLI, tumor IGF-I content, serum IGF-I concentration. The mean tumor TLI values before and after rhGH were 1.3% and 2.6% respectively; median tumor and serum IGF-I levels before rhGH were 4.64 ng/g and 63.5 ng/ml respectively; after the administration of rhGH median tumor IGF-I content was 1.8 and median serum IGF-I level was 112 ng/ml. These data suggest that, in vivo, rhGH stimulates breast cancer cell proliferation; the mitogenic stimulus is likely due to the local production of IGF-I induced by rhGH.

Relationship of variations in tumor cell kinetics induced by primary chemotherapy to tumor regression and prognosis in locally advanced breast cancer.

The relationship of changes in 3H-thymidine labelling index (TLI) induced by primary chemotherapy to tumor response and relapse rate in 36 patients with previously untreated locally advanced breast cancer (LABC) was analyzed. All patients received primary chemotherapy (3 cycles FAC), followed by mastectomy and subsequent adjuvant chemotherapy (3 FAC alternated with 3 CMF). Tumor TLI was evaluated immediately prior to primary chemotherapy and at the time of mastectomy. Median pretreatment TLI was used to discriminate between tumors with a high or low proliferative rate. Clinical objective response to primary chemotherapy was 83% in patients with high TLI and 56% for those with low pretreatment TLI (p = 0.06). Primary chemotherapy induced a > or = 50% reduction of the proliferative rate in 83% and 39% of the tumors with high and low pretreatment TLI, respectively (p = 0.006). Patients were classified into 4 groups according to TLI values both before and after primary chemotherapy: patients who remained in the high TLI group after primary FAC had the highest response rate (100%) and the lowest 2-year relapse rate (20%). These data suggest that: a) improved response to aggressive cytotoxic treatment occurs in tumors with high TLI at diagnosis; b) there is a significant correlation between TLI changes induced by primary chemotherapy and pretreatment proliferative activity; c) patients who remain in the high TLI group after primary chemotherapy are more likely to benefit from subsequent adjuvant systemic therapy.

Phase II study of weekly mitoxantrone, 5-fluorouracil, and leucovorin in metastatic breast cancer.

A phase II study to test the toxicity and the efficacy of a weekly combination of Mitoxantrone, 5-Fluorouracil and L-Leucovorin (MFL) was carried out in 43 patients with metastatic breast cancer. Chemotherapy consisted of mitoxantrone 4 mg/m2, 5-fluorouracil 375 mg/m2, and L-leucovorin 100 mg/m2 on day 1, weekly. Patient characteristics were: median age 53 years (range 36-65); estrogen receptor (ER) status was known in 26 patients and of these 15 (57.7%) patients were ER-positive and 11 (42.3%) ER-negative. Of the 43 patients, 25 (58.1%) and 18 (41.9%) patients had received prior adjuvant chemotherapy and prior adjuvant endocrine treatment, respectively. MFL was administered to 22 (51.1%) patients as first line chemotherapy for advanced disease, while 21 (48.9%) patients had received 1 to 2 cytotoxic regimens for metastatic disease. The dominant sites of metastases were: soft tissue in 11 (25.5%) patients, bone in 8 (18.6%) patients and viscera in 24 (55.9%). All patients were assessable for toxicity: only 8 patients experienced WHO grade 3 leukopenia. Thrombocytopenia, diarrhea, stomatitis, and nausea/vomiting were negligible. Anemia and alopecia were not observed. Thirty-nine patients were assessable for response: overall response rate was 28.2% (complete response 7.7% and partial response 20.5%). Median duration of response was 12 months (range 6-34). Patients with no prior anthracyclines had a 42.1% response rate compared to 15% in patients who had received anthracyclines. Median overall survival of the 43 patients was 6 months (range 1-34). Weekly MFL is a well-tolerated and a moderately effective regimen for the treatment of metastatic breast cancer.

Breast-cancer in the elderly - detection and treatment modalities in 341 women.

Elderly cancer patients are generally excluded from entry to clinical trials;and often managed inadequately or based on individual experience. We have retrospectively determined tumor detection modality, diagnostic and staging work-up, delay in referral and therapeutic approaches in 341 women with breast cancer aged over 70 years. Fifty-eight per cent of patients were in the 70-75 group of age. Our data suggest that tumor is detected during medical visit or hospitalization for reasons other than breast cancer in 63.1% elderly women with 74.1% of tumors diagnosed on stage I+II disease; the interval between patient's awareness of a breast nodule and first diagnostic and/or therapeutic intervention was less than 3 months in 51.4% and between 3 and 6 months in 20.7% of patients. Most of our patients received adequate treatment although in 18.6%, 26.8% and 18.2% of stage Il, III and IV respectively systemic treatment was not administered after surgery. A large proportion (22.3%) of patients received Halsted mastectomy and only 11.1% conservative surgery. We suggest breast examination should be encouraged, screening program should be extended after the age of 70 years and systemic treatment should be evaluated in elderly patients.

Analysis of time to response to chemotherapy in 316 metastatic breast cancer patients.

Chemotherapy is a major tool for metastatic breast cancer treatment. In this study, a series of 316 patients have been analyzed to evaluate the time needed to reach tumor response by means of combination chemotherapy. Twenty-five percent of patients responded within 3 months and virtually all responses occurred within 7.5 months. The time curves of response (any) and best response are superimposable. A subset analysis has shown that the following pretreatment characteristics predict a significantly longer time to response: prior exposure to adjuvant chemotherapy, nodal positivity at diagnosis, no previous endocrine treatment and osseous metastases.

Lymphoblastoid interferon in advanced breast cancer: a phase II study.

Thirty-two metastatic breast cancer patients entered a phase II study in order to evaluate the toxicity and the clinical activity of lymphoblastoid interferon (IFN). The treatment was divided into two phases, induction and maintenance. During the first, patients were submitted to lymphoblastoid IFN at the dose of 3 MU die intramuscularly for 4-8 weeks; during maintenance treatment IFN was given at the same dosage, intramuscularly, every other day until progression. Five patients with inadequate follow-up were excluded from disease evaluation, thus 27 patients were evaluable for response. No complete response was observed; one patient achieved a partial response and 15 patients disease stabilization. Median time to progression in patients with partial response or stable disease was 11 weeks (range 2-32). Five patients with soft tissue metastases were biopsied before and after 1-2 months of treatment in order to perform Labelling Index and hormonal receptor status determinations. No significant modification was observed.

Serum CEA, CA 15-3, and MCA in breast cancer patients: a clinical evaluation.

With the aim of investigating the clinical usefulness of CEA, CA 15-3, and MCA serum levels, we studied 143 women whose breast cancer was submitted to serial tumor marker determinations: 79 women had stage I-II tumors and were undergoing follow-up after local and adjuvant treatment; 64 women presented metastatic lesions. Among the stage I-II patients, 63 women remained disease-free during the observation period and 16 developed metastases. In 13 out of 16 patients, tumor markers were elevated and in 11 out of 16 patients the increased tumor markers were the first sign of disease progression. Among metastatic patients, 49 presented increased tumor markers and 15 normal value. Moreover, we observed a decrease or normalization of tumor markers in patients responding to treatment and increased values in progressive disease. No correlation was noted between site of disease and tumor markers. We concluded that tumor markers are of clinical value in the detection of metastasis and may be useful in monitoring response to treatment in metastatic patients.