Conventional versus cytokinetic polychemotherapy with estrogenic recruitment in metastatic breast cancer: results of a randomized cooperative trial.

Diethylstilbestrol (DES) can induce a recruitment into the proliferative pool of previously resting breast cancer cells in vivo. In order to verify if estrogenic recruitment could result in a larger tumor cell killing by chemotherapy, 117 patients with metastatic breast cancer were randomized to receive CEF (cyclophosphamide, 600 mg/m2; epidoxorubicin, 60 mg/m2; and 5-fluorouracil, 600 mg/m2 on day 1); DES-CEF (cyclophosphamide, 600 mg/m2 on day 1; DES, 1 mg orally on days 5, 6, and 7; and epidoxorubicin, 60 mg/m2, and 5-fluorouracil, 600 mg/m2, on day 8) every 21 days. No significant difference in objective response rates, survival, or progression-free survival was seen between the two regimens. Patients in the DES-CEF arm experienced a higher complete response (CR) rate (24.1% v 16.1%), which reached statistical significance in the case of soft-tissue metastasis (48% v 27.3%; P less than .05) and estrogen receptor-negative tumors (35.7% v 11.1%; P less than .025). Survival and progression-free survival of patients refractory to treatment were not worsened by estrogenic recruitment. In the subset of patients failing after adjuvant polychemotherapy, DES-CEF unexpectedly induced a significantly longer survival (greater than 802 days v 375 days; P = .029) and progression-free survival (239 days v 192 days; P = .041) than CEF. The DES-CEF regimen was more myelotoxic, and 43.3% of the DES-CEF cycles had to be delayed because of leukopenia in comparison with 11.8% of the CEF cycles (P less than .0001). In conclusion, chemotherapy with estrogenic recruitment was able to induce more CRs in certain subsets of patients and a significant prolongation in survival and progression-free survival of patients failing after adjuvant polychemotherapy. These results have been achieved despite a significantly lower dose intensity of chemotherapy.

Sequential versus alternating chemotherapy and radiotherapy in stage III-IV squamous cell carcinoma of the head and neck: a phase III study.

A cooperative randomized study was begun in August 1983 to compare a sequential program of induction chemotherapy followed by definitive treatment, arm A, with an alternation of chemotherapy and radiotherapy (three courses of 20 Gy in ten daily fractions), arm B. The same chemotherapy was used in both arms: 6 mg/m2, vinblastine, hour 0; 30 mg, bleomycin, hour 6; 200 mg, methotrexate, hours 24 to 26; 45 mg, leucovorin, hour 48. One hundred sixteen patients entered the study, 55 in arm A and 61 in arm B. The patients all had previously untreated squamous cell carcinoma of the head and neck (SCCHN). Forty-five patients had stage III and 71 had stage IV disease. The two arms were fully comparable. As of April 1986, 116 patients were evaluable for survival, while 112 were evaluable for toxicity and 105 for response. Response analysis shows that there were 14 complete responses (CR) and 11 partial responses (PR), for an overall response rate (ORR) of 52% in arm A, and 30 CRs and seven PRs, for an ORR of 64.9% in arm B. The difference in terms of CR between the two arms was statistically significant (P less than .03). Progression-free survival (PFS) was also statistically different, with an advantage for arm B (P less than .05), but without differences in overall survival. Arm B correlates with a significant increase in mucositis compared with arm A (P less than .001).

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.

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.

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.

Lonidamine in metastatic breast cancer.

Lonidamine belongs to a new class of antineoplastics agents, since it does interfere with cell energy processes. When administered as single agent in metastatic breast cancer, it produces moderate therapeutic effects. The pattern of toxicity includes myalgias, asthenia, testicular pain, and gastrointestinal discomfort. No myelosuppression was demonstrated in phase I-II studies. Since the peculiar mechanism of action and side effects are not overlapping with those of standard chemotherapeutic agents, combination of lonidamine with chemotherapy is currently under investigation in advanced breast cancer. Moreover, the potentiation of radiotherapy by lonidamine could be of interest in palliating symptomatic lesions from 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.

In vivo manipulation of human breast cancer growth by estrogens and growth hormone: kinetic and clinical results.

Since 1983, a series of experimental and clinical studies have been carried out on the possibility of enhancing the chemotherapy effectiveness in breast cancer by expanding the fraction of cycling cells. Theoretically estrogens should recruit breast cancer cells and this fact should result in a higher killing efficiency of antiproliferative drugs. Actually it has been clearly shown, by means of the thymidine labeling index and primer-dependent alpha-DNA polymerase assay, that low doses of diethylstilbesterol are able to increase the tumor proliferative activity of human breast cancer in vivo (estrogenic recruitment). Three randomized trials have been carried out (one in locally advanced and two in metastatic breast cancer) comparing conventional polychemotherapy vs chemotherapy with estrogenic recruitment. Only limited advantages have been observed in these trials. Searching for new modalities of kinetic manipulation of tumors, recombinant human growth hormone has been employed in a pilot study: the preliminary results indicate that it largely enhances tumor proliferative activity, suggesting the possibility of employing a growth factor system to increase chemosensitivity.

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.

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.

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.

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.

Intensive chemotherapy with cisplatin, mitoxantrone, methotrexate and vincristine in metastatic breast cancer.

Eleven patients (pts) with advanced refractory breast carcinoma were treated with combination chemotherapy (Planovin) including mitoxantrone 10 mg/m2 on day 1, cisplatin 60 mg/m2 on days 1-2, methotrexate 200 mg/m2 on day 15, vincristine 2 mg on day 15, leucovorin 15 mg/m2 on days 15-16 every 3 weeks. Five patients (41%) achieved an objective response with one complete regression. The median duration of response was 4.5 months and the median duration of survival was 8 months. Drug related toxicity consisted mainly of leukopenia (8 pts), nausea and vomiting (6 pts), anemia (7 pts) and thrombocytopenia (4 pts).

Tamoxifen and alpha interferon in advanced breast cancer.

Thirteen pretreated advanced breast cancer patients received a combination of alpha interferon 5 million IU every 2 days, subcutaneously, plus tamoxifen 10 mg 3 times daily, until disease progression. The objective response rate was 15.4%: 1 patient achieved a complete response, 1 a partial response and 11 demonstrated stable disease; half of the patients were receptor negative and/or pretreated with hormonotherapy. Durations of response were 16 and 26 months for the CR and PR patients respectively; median progression-free survival was 4 months (range 0-26). Toxicities were registered according to WHO criteria: 4 patients stopped the treatment with interferon because of severe flu-like symptoms, while in the others the combination was generally accepted with good tolerance.

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.

[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.