E. Garcia-Giralt

BREAST TUMOUR RESPONSE TO PRIMARY CHEMOTHERAPY PREDICTS LOCAL AND DISTANT CONTROL AS WELL AS SURVIVAL

The purpose of the present paper was to evaluate correlations between clinical response to chemotherapy and outcome in a subgroup analysis of premenopausal patients with tumours considered too large for breast conserving surgery, treated with primary chemotherapy (n = 200) from a previously published trial (Scholl S.M., Fourquet A., Asselain B, et al. Eur J Cancer 1994, 30A, 645-652). Objective response rates amounted to 65% following four courses. In a multivariate Cox regression analysis, comparing seven parameters, the following variables were associated with poor survival: clinically involved nodes [N1b:RR: 2.7 (95% CI 1.3-5.3)], the failure to respond to chemotherapy [D:RR: 2.62 (95% CI 1.3-5)] and a raised S phase fraction [SPF > 5%: RR: 2.4 (95% CI 1.2-5)]. Parameters associated with increased metastatic recurrence rates, by order of entry in the model, were: young age [< 35: RR: 2.46 (95% CI 1.2-5)], large clinical tumour size [T3: RR: 2.02 (95% CI 1.2-3.4)], poor histological grade (SBR III: RR: 1.93 (95% CI 1.1-3.3)] and the failure to respond to chemotherapy [D: RR: 1.91 (95% CI 1-3.4)]. The assessment of both tumour cell proliferation rates as well as possibly drug resistance markers (although not available in the present study) should be helpful in selecting patients likely to benefit from intensified chemotherapy regimens. The most accurate predictor of response in the present study appeared to be the response to chemotherapy treatment itself.

Prognostic factors in inflammatory breast cancer and therapeutic implications

223 inflammatory breast cancer patients were diagnosed at the Institut Curie between 1977 and 1987. Patients received chemotherapy and radiation treatment according to three consecutive randomised trials. Five- and 10- year survival rates were 41 and 32%, respectively. Disease-free interval rates were 25.5% at 5 years and 19% at 10 years. Parameters significantly linked with a pejorative prognosis in a multivariate analysis were: diffuse erythema, lymph node involvement, chest wall adherence, and age above 50 years. When therapeutic response parameters were included in the multivariate analysis, the five most important prognostic factors in order of significance were complete tumour regression after completion of induction treatment (at 8 months), complete regression of inflammatory symptoms after 3 months of neoadjuvant chemotherapy, limited erythema at presentation and, less significantly, complete regression of inflammatory symptoms at 8 months and tumour regression at 3 months. In conclusion, patients who achieved a rapid and complete remission had a better prognosis than patients who had an incomplete response to chemotherapy. High-dose chemotherapy and reversal or prevention of drug resistance will be evaluated in future trials. Detailed information on the biology of this disease should allow the design of new strategies aiming to improve patient management.

Clinical phase II trial of recombinant dna interferon (interferon alfa 2b) in patients with metastatic malignant melanoma

Twenty‐four patients with historically proven metastatic malignant melanoma were included in a Phase II trial of human DNA recombinant interferon (rDNA IFNα2). They were given 10 × 106 IU of IFNα2 subcutaneously three times a week until progression of disease or major intolerance developed. Twenty‐ two patients were evaluable for toxicity and response. General manifestations of intolerance were seen in all the patients. Hematologic toxicity was seen in six patients and therapy had to be interrupted in one patient. Mild liver toxicity was seen in most patients after 2 weeks of treatment. These manifestations disappeared within 2 weeks after treatment was discontinued. A partial response was seen in four cases lasting 2, 4, 4, and 5 months, respectively. There were two complete responses (one skin, one lymph node metastasis) lasting 20 and 6 weeks, respectively. These results indicate a potential role for rDNA IFNα2 in treating patients with metastatic malignant melanoma. However, further trials are required to determine the optimal dose and schedule of administration and modalities of combination. Cancer 58:215–218, 1986.

Treatment of metastatic malignant melanoma with recombinant interferon alfa-2b

SummaryTwenty-six patients with histologically proven metastatic malignant melanoma were included in a phase II trial of interferon alfa-2b (Intron A; Schering-Plough). Patients were given 10 × 106 IU/m2 of interferon alfa-2b subcutaneously three times a week until major intolerance or progression of disease.General signs of intolerance were seen in all patients; hematological toxicity with leukopenia (below 1,800/mm3) and/or thrombocytopenia (below 600/mm3) was seen in six patients and therapy was interrupted in one patient. Mild liver toxicity was seen in most patients after two weeks of treatment. These manifestations disappeared 1–2 weeks after treatment was discontinued. Twenty-four patients were evaluable for response. There were two complete responses; one skin and one lymph node going into remission for 12 and 12.5 months respectively. A partial response was observed in five cases lasting 1, 1.8, 2, 3 and 5 months respectively.These results indicate a potential role for interferon alfa-2b in treating patients with metastatic malignant melanoma, however, further trials are required to determine the optimum dose and schedule of administration and use of interferon alfa-2b in combination with cytotoxic drugs.

Protracted continuous infusion of 5-fluorouracil in combination with doxorubicin, vincristine, and oral cyclophosphamide in advanced breast cancer.

Several studies suggest that protracted continuous infusion constitutes an important way to optimize the dose and the efficacy of 5-fluorouracil (5-FU) in metastatic cancer. Eighty-three women aged 27-76 (median age 55) with metastatic breast cancer were treated every 4 weeks with a continuous ambulatory venous infusion of 5-FU 350 mg/m2/day and oral cyclophosphamide 100 mg/m2/day over 15 days. The continuous therapy was associated with a weekly administration of vincristine (0.8 mg/m2) and doxorubicin (15 mg/m2) on day 1, day 8, and day 15. Cycles were repeated every 28 days. Thirty-four patients were treated in first-line metastatic chemotherapy and 49 in second-line. Toxicities included: mucositis (grade > or = 2) 23%, diarrhea (grade > or = 2) 7%, a hand-foot syndrome (grade > or = 2) 9%, alopecia (grade 3) 21%, neurological (grade > or = 2) 4%, grade 3 and 4 leukopenia 29%, and grade 3 and 4 thrombopenia 8%. Heart toxicity was only 3%. Catheter infection was observed in 1 case and 7 patients experienced thrombosis. The overall objective response rate (OR) was 48% and the complete response rate was 23%. The median duration of response was 10 months. The median survival was 16 months. Activity was better in naive than pretreated women (respectively, 55% and 42% of OR, p = 0.21). Analysis of responses according to the metastatic sites shows the pronounced efficacy on soft tissue diseases (skin recurrences 42%, lymph nodes 52%), and also in visceral metastases (hepatic 36%, lung 34%).

Interferons in Breast Cancer

Because of its antiviral, immunomodulating and antiproliferative properties, Interferon was tested as an antitumor agent.