Bernard Chevallier

Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate.

Between July 1988 and May 1990, we treated 45 women with newly diagnosed, unilateral, nonmetastatic, inflammatory breast cancer with an intensive neoadjuvant chemotherapy regimen (FEC-HD) repeated every 21 days, followed by surgery or radiation therapy. Evaluation of efficacy performed 3 to 4 weeks after at least 2 cycles showed disappearance of inflammatory signs in 91% of the patients and improvement in the remaining 9%. With regard to primary tumor and lymph nodes, there were 13 (28.9%) clinical complete responses, 30 (66.6%) partial responses, and 2 (4.5%) without change. No progressive disease was observed. Hematologic toxicity from this regimen was high with grade 4 neutropenia observed at day 14 in 100% of the patients. Re-treatment at day 21 was possible in 83% of the cycles. Grade 1 or 2 infections occurred in 102 cycles out of 176 (57.9%). Grade 3 infections were seen in 9 cycles (5%). No septicemia or septic shock occurred. No toxic death occurred. After induction chemotherapy, locoregional treatment consisted of modified radical mastectomy in 39 patients and radiotherapy alone in 6. The mastectomy specimen showed no residual invasive tumor (primary tumor and lymph nodes) in 10 cases (25.6%). Two patients judged as partial responders were in fact histologic complete responders. The clinical and histological response rates observed appeared very promising. For this reason we are currently testing FEC-HD with or without GCSF in a randomized multicenter trial with correction of neutropenia, disease-free survival, and overall survival as main end points.

Docetaxel is a major cytotoxic drug for the treatment of advanced breast cancer: a phase II trial of the Clinical Screening Cooperative Group of the European Organization for Research and Treatment of Cancer.

PURPOSE This trial investigated the toxicity and efficacy of docetaxel as first-line chemotherapy in women with heavily pretreated advanced breast cancer. PATIENTS AND METHODS From April 1992 to August 1992, 35 patients with advanced breast cancer from 29 to 65 years of age with a performance status of 0 to 2 were entered onto the study. Docetaxel 100 mg/m2 was administered every 3 weeks as a 1-hour infusion on day 1 without routine premedication for hypersensitivity reactions. Thirty-one patients were assessable for response. Previous adjuvant chemotherapy had been given to 11 patients. RESULTS Five complete responses (CRs) and 16 partial responses (PRs) were observed, for an overall response rate of 67.7% (95% confidence interval, 49% to 83%). A CR occurred at 13 of 45 assessable sites (four liver, two lung, three breast, three lymph node, and one skin). The median duration of response was 44+ weeks, the median time to disease progression 37+ weeks, and the median overall survival time 16+ months. Among 34 patients assessable for toxicity (177 cycles; median, five cycles per patient), the following side effects were reported: nadir neutropenia grade 3 (three patients); grade 4 (31 patients); no grade 3 to 4 infection, acute hypersensitivity-like reaction (10 patients); grade 2 to 3 alopecia (all patients); and grade 2 to 3 nausea and vomiting (six patients). Fluid retention occurred in 26 patients and consisted of weight gain, edema alone (15 patients), or edema associated with serous effusion (11 patients). This side effect led to treatment discontinuation in 16 of 21 responding patients after a median of five cycles and a median cumulative dose of docetaxel of 574 mg/m2. CONCLUSION Our data suggest that docetaxel has major antitumor activity when used as a single cytotoxic agent as first-line chemotherapy in advanced breast cancer.

Lenograstim prevents morbidity from intensive induction chemotherapy in the treatment of inflammatory breast cancer.

PURPOSE To compare the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) versus its inert vehicle in patients with unilateral nonmetastatic inflammatory breast cancer treated with fluorouracil, epirubicin, and cyclophosphamide high-dose (FEC-HD) neoadjuvant chemotherapy. PATIENTS AND METHODS One hundred twenty patients have been enrolled by nine French centers in this double-blind, parallel-group, vehicle-controlled study to compare at each cycle subcutaneous lenograstim (5 micrograms/kg/d) with placebo given from day 6 to day 15 after the induction chemotherapy (day 1 to day 4, fluorouracil 750 mg/m2 continuous intravenous [IV] infusion; day 2 to day 4, epirubicin 35 mg/m2 and cyclophosphamide 400 mg/m2 both IV push). Four cycles were planned every 3 weeks before locoregional treatment. Patients with febrile neutropenia remained blinded for the subsequent cycles. RESULTS Lenograstim significantly reduced the duration of neutropenia at less than 0.5 x 10(9)/L and less than 1 x 10(9)/L to a median duration of 2 and 3 days, respectively, as compared with 5 and 7 days in the placebo group. This translated into a statistically significant reduced incidence of microbiologically documented infections, and a decreased need for rehospitalizations for infectious events and antibiotic use. Clinical objective tumor response rate observed after four cycles was 89.6% and 93%, respectively, in the placebo and treated groups. Mild transient bone and injection-site pain, myelemia, and hyperleukocytosis were the most frequently reported adverse events associated with lenograstim. CONCLUSION Lenograstim is safe and effective to reduce morbidity associated with FEC-HD neoadjuvant chemotherapy in inflammatory breast cancer. Response rate is not affected.

Neuroendocrine primary small cell carcinoma of the breast. Report of a case and review of the literature.

One case of breast neuroendocrine primary small cell carcinoma with light microscopic and immunohistochemical findings is reported. The patient died of unrelated disease 21 months after diagnosis and treatment by modified radical mastectomy, radiotherapy and subsequent chemotherapy. Immunohistochemical studies revealed cytokeratin and neuroendocrine markers (chromogranin, neuron-specific enolase) immunostaining on tumoral cells. Expression for neuropeptides (met-enkephalin, leu-enkephalin, β-endorphin) and CALLA antigen was found. Based on this case report and six other previously reported cases, breast neuroendocrine primary small cell carcinoma appears to be a very aggressive tumor for which no firm conclusions regarding treatment can be drawn.

Results of a European Organization for Research and Treatment of Cancer/Early Clinical Studies Group Phase II Trial of First-Line Irinotecan in Patients With Advanced or Recurrent Squamous Cell Carcinoma of the Cervix

PURPOSE To determine the efficacy and tolerability of irinotecan (CPT-11) in advanced or recurrent cervical carcinoma. PATIENTS AND METHODS Eligible patients had histologically confirmed, inoperable, progressive, metastatic or recurrent squamous cell cervical carcinoma and had received no radiotherapy in the preceding 3 months and had never received chemotherapy. The initial irinotecan dosage of 350 mg/m(2) every 3 weeks was modifiable according to toxicity. Treatment continued for six cycles after complete response, or until disease progression or excessive toxicity after partial response, or for three additional cycles in the case of stable disease. Patients were stratified into group A (>/= one measurable lesion in a previously unirradiated area, with or without progressive disease in irradiated fields) or group B (measurable new lesion[s] in an irradiated field). RESULTS Fifty-one of 55 enrolled patients were eligible for inclusion (median age, 47 years; range, 30 to 71 years). The response rate was 15.7% (95% confidence interval [CI], 7.0% to 28.6%) overall, 23.5% (95% CI, 10.7% to 41.2%) for group A (complete response, 2.9%), and zero for group B. The median time to progression and median survival were 4.0 and 8.2 months for group A and 2.5 and 4.2 months for group B, respectively. The major grade 3/4 toxicities for groups A and B were diarrhea (24.3% and 55.5%, respectively) and neutropenia (24.3% and 33.3%, respectively). There were four toxicity-related deaths, three in group B. Patients with no prior external pelvic irradiation experienced fewer grade 3 and 4 adverse events. CONCLUSION Irinotecan is effective in treating cervical squamous cell carcinoma if disease is located in an unirradiated area. Because of toxicity, a reduced dose is advised for patients previously treated with external pelvic irradiation.

Inflammatory Breast Cancer Outcome With Epirubicin- Based Induction and Maintenance Chemotherapy Ten-Year Results From the French Adjuvant Study Group GETIS 02 Trial

The authors evaluated the long‐term efficacy and side effects in patients with nonmetastatic, unilateral, inflammatory breast cancer (IBC) who received homogeneous treatment with intensive induction chemotherapy followed by a maintenance regimen.

A clinical screening cooperative group phase II evaluation of lobaplatin (ASTA D-19466) in advanced head and neck cancer.

SummaryWe evaluated the efficacy and tolerability of lobaplatin, a new platinum compound, given at the dose of 50 mg/m2 by i.v. bolus every 4 weeks, in 49 patients with advanced and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). One complete and 2 partial responses were observed in 43 eligible patients for an overall response rate of 7% (95% confidence interval: 1–19%). The duration of responses was 11, 16 and 32 weeks. Toxicities of WHO grade ≥ 3 were hematologic: thrombocytopenia in 26%, granulocytopenia in 12% and anemia in 12% of patients. There was no therapy-related death. Nausea/vomiting, diarrhoea and paresthesia were mild and rare. In conclusion, lobaplatin was well tolerated, but its efficacy in advanced SCCHN at the presented dose and schedule, was marginal.

Current status of Taxotere® (docetaxel) as a new treatment in breast cancer

SummaryTherapy for advanced breast cancer has not improved significantly in recent years, remaining strictly palliative in nature and intent. One approach to increase the effectiveness of the treatment is the introduction of active new drugs. Taxotere® (docetaxel) is a taxoid derivative isolated from the needles of the European yew,Taxus baccata. Taxotere promotes the assembly of microtubules and inhibits their depolymerization. One EORTC Clinical Screening Group (CSG) phase II trial using Taxotere at 100 mg/m2, 1 hour infusion without routine premedication for hypersensitivity reactions, in first line chemotherapy, indicates a high anti-tumor activity: 5 complete and 18 partial responses in 32 patients assessable for response (overall response rate 72%, 95% CI 53%–86%). Other studies confirm this activity in first line and second line chemotherapy for advanced disease and in patients who are refractory to anthracycline containing regimens. Grades III and IV neutropenia without major infection, and grades I and II skin toxicity, were frequently observed adverse events. A fluid retention syndrome (chronic cumulative and non life-threatening toxicity) has been noted in patients treated with Taxotere. Methods for controlling fluid retention — dose reduction to 75 mg/m2 (which has little effect) or routine premedication from the start of treatment — are currently being studied.

Phase II trial of idarubicin (4-demethoxydaunorubicin) in advanced breast cancer

Abstract A phase II trial of idarubicin (IDR-4 demethoxydaunorubicin) was carried out in patients with advanced breast cancer. A dose of 45 mg/m 2 was given orally once every 3 weeks. A total of 66 eligible patients were entered into the trial, 56 of whom were evaluable for response ( 65 were evaluable for toxicity at least). Therapeutic activity was demonstrated with an overall objective response rate of 21% ( 95% CI: 11–32% ). When used as a first-line treatment, the response rate was 33% ( 95% CI: 9–57% ) but this dropped to 17% when the treatment was administered after chemotherapy. Nausea-vomiting was the most frequent and severe non-hematological toxicity observed (WHO grade 3–4: 29% ). Loss of hair was noticed in 48% of the patients but only 4% suffered from complete alopecia. Moderate myelotoxicity was reported but no cardiac dysfunction was noticed. IDR could be very advantageous as compared to other anthracyclines, due to its simplicity of administration associated with the lack of risk of extravasation or chemical phlebitis and also the possibility of it being able to reduce cardiotoxicity. Even if the equiefficacy of IDR and DXR has not, as yet, been clearly demonstrated, IDR should be chosen with preference to DXR when administration is not suitable.

Phase I-II trial of intensification of the MAID regimen with support of lenograstim (rHuG-CSF) in patients with advanced soft-tissue sarcoma (STS).

This study was conducted to determine the maximum tolerated dose of an intensified MAID (mesna, adriamycin, ifosfamide, dacarbazine) regimen with the support of lenograstim in patients with advanced soft tissue sarcomas. Following 1 cycle of MAID at the standard dose, four patients were to be treated at each of five dosage levels: +25%, +45%, +65%, +85%, +100%. Sixteen patients were treated. Because there were no significant differences in hematologic toxicity between patients receiving lenograstim 5 or 10 microg/kg/day (levels 1-5 and 1-10), the data were pooled for comparison with level 2. The median duration of absolute neutrophil count < 0.5 x 10(9)/l was 3 days at level 1 and 7 days at level 2 (p < 0.01). The median platelet nadir was 25 x 10(9)/l at level 1 and 10 x 10(9)/l at level 2 (p < 0.01). The median duration of toxicity-related hospitalization was 3.5 days and 11 days at levels 1 and 2, respectively, (p < 0.001). Mucositis > or = grade III occurred after 3/29 cycles at level 1 and 10/15 cycles at level 2 (p < 0.001). After 4 cycles at level 1, 8/8 patients still had performance status scores < or = 2, and only 4/8 had performance status scores < or = 2 after the second cycle at level 2. Lenograstim enabled an increase of 25% of the MAID regimen. At higher dose levels, severe mucositis and deterioration in performance status were dose limiting.