LH-RH analogues in the treatment of young women with early breast cancer: long-term follow-up of a phase II study.

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.

Adjuvant Ovarian Suppression, High-dose Chemotherapy and Immunotherapy for Premenopausal Patients with High-risk Breast Cancer.

BACKGROUND: Premenopausal patients with breast cancer and more than 10 positive axillary nodes (BC>10) have a poor prognosis: In these patients the best adjuvant therapy (CT) has not yet been established. PATIENTS AND METHODS: Forty-two BC>10 received, in sequence, the following adjuvant treatments: luteinizing hormone releasing hormone (LH-RH) analog for 5 years; anthracycline-based induction chemotherapy; radiation therapy; platinum-based high-dose CT, with autologous bone marrow transplantation; immunotherapy with interleukin 2 (IL2) and 13-cis retinoic acid (RA); anastrazole given 5 years to estrogen receptor-positive patients. Primary endpoints of the study were disease-free survival (DFS) and overall (OS) survival. A secondary endpoint was toxicity. RESULTS: The median age of patients was 41 years, and the mean number of positive axillary nodes was 14. Estrogen and progesterone receptors were positive in 57% and 29% of patients respectively, while 14% of patients had triple-negative disease. With a median follow-up of 120 months for patients remaining alive at the end of study, median DFS and OS, had not yet been reached. The 20-year DFS and OS rates were 63.8%, and 81.6%, respectively. One to two years after the end of the therapy, three patients had had four full-term pregnancies. CONCLUSION: Treatment with LH-RH analog, high-dose CT, peripheral blood progenitor cells and IL2 with RA for patients with BC>10 is feasible, has moderate toxicity, while preserving ovarian function, seems to improve the expected DFS and OS for these high-risk patients.

Interleukin-2 and 13-cis retinoic acid in the treatment of minimal residual disease: a phase II study.

Interleukin-2 (IL-2) which has no cross-resistance with chemotherapy, has given responses in tumors resistant to chemotherapy, and shown to be more effective when tumor burden is low. 13-cis retinoic acid (RA) has immunomodulatory properties, potentially synergistic with IL-2. The objective of this pilot phase II study was to verify the immunomodulatory properties, activity and toxicity of outpatient immunotherapy with subcutaneous low dose IL-2 and oral RA, identified in a previous phase-I study, in patients with advanced solid cancer in whom a response or stable disease as a result of standard chemotherapy had been achieved. Eighty patients with advanced solid tumors after standard chemotherapy, were treated with IL-2: 1.8 x 106 IU and RA: 0.5 mg/kg for 5 days/week for 2 consecutive cycles of 3 weeks, with a 1-week rest, for up to 1 year. A total of 511 courses of IL-2/RA therapy were administered (median 6.4 per patient). Tumor markers, T4/T8 ratio and NK were monitored every 2 months. Response evaluation was carried out every 4 months. After a median follow-up time of 31 months there was a statistically significant improvement in the number of total lymphocytes, T4/T8 ratio and NK after IL-2 and RA therapy. Responses and disease stabilization were maintained for a median time of 19.3 months. Six patients were converted from partial to complete response, while 5 patients progressed. Median survival time was not reached yet. Grade 2 cutaneous toxicity and fever were observed in 29 and 13% of patients, respectively. These preliminary data show that after chemotherapy the administration of low-dose subcutaneous IL-2 and oral RA is feasible and has low toxicity. A sustained increase in the immunological parameters known to be prognostically relevant was observed and a clear benefit on tumor response from immunotherapy was obtained in 7.5% of patients.

Gemcitabine, ifosfamide and vinorelbine in advanced non-small cell lung cancer: a phase II study.

BACKGROUND: The objective of this phase II study was to determine the activity and toxicity of gemcitabine, ifosfamide and vinorelbine, in the treatment of patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naïve patients with unresectable, stage IIIB and stage IV NSCLC, measurable lesions and an Eastern Cooperative Oncology Group (ECOG) performance status < or = 3, were entered into the trial. The treatment consisted of ifosfamide 1500 mg/m2 on days 1 to 3 with vinorelbine 25 mg/m2 and gemcitabine 1000 mg/m2 on days 3 and 8, every 3 weeks. RESULTS: Fifty-four patients with stage IIIB (24%) and stage IV (76%) were enrolled into the trial. The median age of the patients was 65 years. The performance status was 0-1, 2 and 3 in 48%, 43% and 9% of patients, respectively. The histology was mainly squamous cell carcinoma (52%), which was poorly-differentiated in 30% of patients. All patients, receiving a total of 249 chemotherapy courses, were assessable for response and toxicity on an intent-to-treat basis. Objective responses included complete response in 3 (5.6%) patients (95% CI: 1.1% to 15.3%), partial response in 26 (48.1%) patients (95% CI: 34.3% to 62.2%), giving an overall response rate of 53.7% (95% CI: 39.6% to 674%). Stable disease was observed in 20 (37%) patients (95% CI: 24.3% to 51.2%) and progressive disease in 5 (9.3%) patients (95% CI: 3% to 20.3%). The median time to progression was 8.8 months (range: 2-55+ months). The median overall survival was 13.2 months (range: 2-55+). The 1-year survival rate was 56% for all patients, comprising 78% and 47% for stage IIIB and stage IV patients, respectively (p=0.088). Myelosuppression was the main side-effect with (WHO) grade 3/4 neutropenia and thrombocytopenia in 56% and 13% of the patients, respectively. CONCLUSION: Our results showed that even patients with a poor performance status may benefit from gemcitabine, ifosfamide and vinorelbine treatment, with acceptable toxicity.

Goserelin as ovarian protection in the adjuvant treatment of premenopausal breast cancer: a phase II pilot study.

The aim of the present trial was to investigate the protective effects on ovarian function, and the efficacy and tolerability of goserelin added to adjuvant chemotherapy for early breast cancer. Following surgical treatment, 64 premenopausal patients with early breast cancer received goserelin 3.6 mg (every 28 days for 1 year) and an adjuvant treatment which was chosen according to the patient's prognosis. Median age was 42 years (range 27-50). ECOG performance status was 0-1 in all patients. Twenty-eight patients (44%) had estrogen receptor (ER)+ tumors and 36 (56%) patients had ER- tumors. Fifty-two (81%) patients had stage II disease and 12 (19%) had stage III disease. Eighteen patients received cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy, 46 patients received an anthracycline-based regimen, and nine of them received high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation. Fifty-one patients (80%) were irradiated. ER+ patients also received tamoxifen for 5 years. Serum estradiol was suppressed to values below 40 pg/ml in all patients. After a median follow-up of 55 months, 86% of patients had resumed normal menses, 84% of patients were disease-free and 94% were alive. The 1-, 3- and 5-year projected recurrence-free survival rates were 100, 81 and 75%, respectively. Five years after treatment one patient had a pregnancy that ended with a normal childbirth. No unexpected adverse events were reported. These data show that the addition of goserelin to adjuvant therapy of premenopausal patients with early breast cancer is well tolerated and protects long-term ovarian function.