Abstract. Based on a series of in vitro data, including the additive and/or synergistic antiproliferative effect of interferon and tamoxifen on breast cancer cell lines, and on clinical reports, we designed a pilot phase II study to test the activity and toxicity of simultaneous administration of ß-interferon (ß-IFN), retinoids (R) and tamoxifen (TAM) as a salvage therapy in a group of patients with metastatic breast cancer (MBC). Herein we describe the outcome of this cohort of patients after a median follow-up of 150 months. Sixty-five stage IV breast cancer patients, 13 pre-treated with hormones, 38 with chemotherapy and 15 with both, received, as a salvage therapy, TAM, ß-IFN and R. Among 65 evaluable patients, 36 achieved a clinical response (55.5%) (95% c.i. 42-67.7%). Toxicity was moderate and mainly hepatic. Median progression-free and overall survival, which did not show any statistically significant difference in patients with different estrogen and progesterone receptor content, were 43 months and 47.9 months, respectively. In conclusion, the study shows that long-term treatment with TAM, ß-IFN and R in MBC is feasible, has moderate toxicity and seems to give a long-term benefit, irrespective of the receptorial status.

Abstract. To prevent premature ovarian failure (POF), high-risk, premenopausal women with early breast cancer were given a luteinizing-hormone releasing hormone (LH-RH) analogue during adjuvant chemotherapy. After an adriamycin-based regimen, patients received radiation therapy concomitant with cyclophosphamide, methotrexate and 5-fluorouracil. An aromatase inhibitor was given to patients positive for the estrogen receptor (ER + ). The median age was 43 years (range, 26-45). Among 200 consecutive patients, 46% had no axillary node, and 54% had a mean of 5.4 positive nodes (range, 1-25); 56% were ER + , 44% were estrogen receptor negative (ER -), 13% were triple negative, and 20 had tumors positive for the oncogene, c-erb-B2 (identified with fluorescent in situ hybridization). After a median follow-up of 105 months (range, 65-180), no patient under 40 years old exhibited POF, while 44% of patients over 40 years old exhibited POF. Eight pregnancies were recorded: 7 at term and 1 voluntary interruption. The 10-year disease-free survival and overall survival rates were 85 and 91%, respectively. These data showed that, in premenopausal patients with early breast cancer, the addition of an LH-RH analogue to adjuvant chemotherapy was well tolerated, prevented POF, and was associated with excellent disease-free survival and overall survival rates. IntroductionBreast cancer in young women is associated with a poor prognosis; in the absence of adjuvant treatment, approximately half of the patients will die of metastatic disease. Ovarian ablation was the first described form of endocrine therapy for treating advanced breast cancer (1). Previous trials have also suggested that ovarian ablation with surgery or radiation therapy could reduce the risk of recurrence in young premenopausal women (2). However, in recent years, adjuvant chemotherapy has become the standard treatment for young premenopausal patients with breast cancer that have a high risk of systemic disease (3).One important aspect of chemotherapy is the toxicity, which can induce premature ovarian failure (POF). POF was reported in 68% of women after cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) regimens, and a POF higher rate was observed in women treated with anthracycline-based regimens (4). This may be a serious problem for young women in reproductive ages. Preserving fertility during adjuvant chemotherapy has been an ongoing endeavor, since 1987 (data on file), when a nulliparous, just married, 33-year-old woman, with high risk of breast cancer underwent anthracycline-based adjuvant chemotherapy. She was treated with buserelin, a luteinizing-hormone releasing hormone (LH-RH) agonist, once daily in a nasal spray, during 6 months of chemotherapy. After chemotherapy and radiation therapy, she completed two full term pregnancies.In the following years, we conducted a clinical trial in premenopausal patients with early breast cancer, where another LH-RH agonist, goserelin was given subcutaneously (3.6 mg) every 28 days for 1 year, in addition to adjuv...

These results support the efficacy and safety of a multi-step sequential treatment in patients with locally advanced, inoperable or incompletely resected Pa and Bt ADKs.

Combining chemotherapy and immunotherapeutic agents such as interleukin-2 and interferon alpha-2b might improve treatment results in metastatic melanoma (MM) patients compared with chemotherapy alone. This prospective study evaluated the potential efficacy of a biochemotherapy regimen followed by maintenance biotherapy for the treatment of MM. Twenty-two patients with stage IV melanoma were treated for 5 consecutive days with cisplatin at 20 mg/m, vinblastine at 1.6 mg/m, and dacarbazine at 160 mg/m. Pegylated interferon alpha-2b at a dose of 50 microg every week, subcutaneous interleukin-2, 1.8 MIU, and oral 13-cis-retinoic acid (13-cis-RA) at 0.5 mg/kg were given 5 days/week for 3 weeks each month during the period of chemotherapy administration. Maintenance biotherapy was continued in patients who had a complete or partial response or disease stability (clinical benefit) after six courses of biochemotherapy. The primary endpoint was response; secondary endpoints were the evaluation of the immunologic parameters, toxicity, progression-free survival, and overall survival. Twelve patients (54.5%) achieved a response, and seven (31.8%) maintained stable disease for at least 6 months with maintenance biotherapy. The median progression-free survival and overall survival were 23.3 and 45.7 months, respectively. The most important toxicities from chemotherapy were grades 3 and 4 neutropenia and thrombocytopenia in 41 and 18% of patients, respectively, whereas grade 2 autoimmune reactions were observed in 21% of patients after maintenance biotherapy. A prolonged enhancement of immunologic function was observed in the 19 patients treated with maintenance therapy. A regimen of six cycles of biochemotherapy followed by maintenance immunotherapy is well tolerated, and shows significant activity in patients with MM.

The purpose of this study was to determine the efficacy and safety of a maintenance immunotherapy regimen administered to patients with recurrent/metastatic squamous cell carcinoma of the head and neck (RMHN) who showed clinical benefit from docetaxel, ifosfamide, and cisplatin chemotherapy (DIP). Every 4 weeks, patients with RMHN received 60 mg/m docetaxel on day 1, and 1200 mg/m ifosfamide and 20 mg/m cisplatin on days 1 to 4. Low-dose subcutaneous interleukin-2 and oral 13-cis-retinoic acid were administered as maintenance immunotherapy to patients who showed a clinical benefit (complete or partial response, disease stability). The primary end point was response; secondary end points were progression-free survival, overall survival, toxicity, and evaluations of lymphocytes, natural killer cells, and serum vascular endothelial growth factor (VEGF). After a median follow-up of 22 months, 263 courses of chemotherapy were administered to the 54 patients. The overall response rate was 59%. Forty-two patients (78%) had a clinical benefit and received 185 courses of maintenance immunotherapy. Median progression-free survival and overall survival were 11.1 and 21.8 months, respectively. Statistically significant, progressive increases in lymphocytes and natural killer cells and a decrease in VEGF were observed in patients treated with maintenance immunotherapy. The toxicity was relatively well tolerated and caused no death. Outpatient administration of DIP, followed by low-dose interleukin-2 and 13-cis-retinoic acid, was generally well tolerated and showed promising activity against RMHN. Longitudinal changes in lymphocytes, natural killer cells, and VEGF might be useful biomarkers for response and survival.