Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial.

BACKGROUND: Tamoxifen, for many years the 'gold standard' in the adjuvant setting for the management of endocrine sensitive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy due to the development of resistance. This provided the rationale for a switching trial with anastrozole, the updated results of which are reported here. PATIENTS AND METHODS: This trial investigated the efficacy of switching to anastrozole for women already receiving tamoxifen. After 2-3 years of tamoxifen treatment, postmenopausal, node-positive, ER-positive patients were randomized to receive either anastrozole 1 mg/day or to continue tamoxifen, 20 mg/day, giving a total duration of 5-years treatment. The primary end point was disease-free survival and secondary endpoints were event-free survival, overall survival and safety. RESULTS: A total of 448 patients were enrolled. At a median follow-up time of 64 months (range 12-93), 63 events had been reported in the tamoxifen group compared with 39 in the anastrozole group [HR 0.57 (95% CI 0.38-0.85) P = 0.005]. Relapse-free and overall survival were also longer in the anastrozole group [HR 0.56 (95% CI 0.35-0.89) P = 0.01 and 0.56 (95% CI 0.28-1.15) P = 0.1]. However, the latter difference was not statistically significant. Overall more patients in the anastrozole group experienced at least one adverse event (209 versus 151: P = 0.000). However, numbers of patients experiencing serious adverse events were comparable (37 versus 40, respectively: P = 0.7). CONCLUSIONS: Switching to anastrozole after the first 2-3 years of treatment was confirmed to improve event-free and relapse-free survival of postmenopausal, node-positive, ER-positive early breast cancer patients already receiving adjuvant tamoxifen.

Adjuvant chemotherapy with high-dose cyclophosphamide, etoposide and cisplatin intensification without progenitor cell support in breast cancer patients with ten or more involved nodes: 5-year results of a pilot trial.

OBJECTIVES: The purpose of this study was to evaluate the clinical efficacy and tolerability of high-dose (HD) chemotherapy with growth factor support in primary breast cancer with extensive nodal involvement. PATIENTS AND METHODS: Fifty-three patients with ten or more involved nodes were recruited and were given three cycles of standard-dose fluorouracil, epidoxorubicin and cyclophosphamide followed by one single course of high-dose CEP (cyclophosphamide, etoposide and cisplatin). No autologous progenitor support was used. RESULTS: Five-year actuarial disease-free and overall survival were 40 and 60%, respectively. High-dose CEP required a median of 22 days of hospitalization and was associated with grade G3--4 nausea and vomiting in two thirds of the cases. Hematological toxicity was comparable to that of high-dose therapies delivered with autologous progenitor support. No therapy-related mortality was observed. CONCLUSIONS The efficacy of treatment was comparable to the best results of conventional therapy, with only a trend for improved survival. High-dose CEP was feasible with acceptable toxicity. Although this regimen does not require stem cell harvesting and storage, it requires clinical support comparable to autotransplantation procedures and side effects are not so manageable to recommend its use outside specialized units.

FEC (5-fluorouracil, epidoxorubicin and cyclophosphamide) versus EM (epidoxorubicin and mitomycin-C) with or without lonidamine as first-line treatment for advanced breast cancer. A multicentric randomised study. Final results.

From May 1991 to December 1996, 326 patients with advanced metastatic breast cancer were enrolled in a multicentre, randomised, phase III clinical trial with four arms. Patients were randomised to receive chemotherapy according to the FEC regimen (5-fluorouracil (5-FU) 500 mg/m2, epidoxorubicin (EPI) 75 mg/m2 and cyclophosphamide (CFA) 500 mg/m2, intravenously (i.v.). every 3 weeks) or the EM regimen (EPI 75 mg/m2, i.v. every 3 weeks; mitomycin C (MMC) 10 mg/m2, i.v. every 6 weeks) or the same regimens with the addition of lonidamine (LND) until disease progression (orally, thrice daily, 150+150+300 mg); a maximum of eight chemotherapy cycles were planned. The aim of the trial was 2-fold: to compare the EM regimen with the commonly used FEC regimen and to evaluate the possible role of the addition of LND. Patients were eligible if they had histologically proven breast carcinoma, metastatic or locoregional relapse with measurable and/or evaluable disease and were aged between 18 and 70 years: 318 patients were considered eligible. Patients with previous anthracycline-based adjuvant chemotherapy or those who relapsed within 6 months after any adjuvant chemotherapy regimen were excluded. Chemotherapy-related toxicity of grade > or = 3 was manageable and there was no significant difference between the arms in terms of haematological side-effects. The impact on heart function was mild. No increased toxicity was observed in the LND arms (apart from myalgias in 27-30% of the cases). A significant increase in the complete response rate was observed for the FEC/EM + LND group (20.4%) versus the FEC/EM group (10.8%). The median survival time and the median time to progression for the overall series were 608 days and 273 days, respectively; EM+/-LND achieved significantly improved survival and time to progression versus FEC+/-LND (P=0.01). This result was confirmed also when the analysis was restricted to patients previously treated with adjuvant CMF schedules. On the basis of these results, we conclude that EM may represent a valuable alternative to FEC for patients requiring a first-line regimen for advanced/ metastatic breast carcinoma, especially in patients previously treated with CMF in an adjuvant setting. Furthermore, we conclude that, in spite of a better complete response rate in the LND arms, as there was no clear advantage in time to progression or survival resulting from the addition of LND to the FEC or EM regimens, the routine use of LND is not warranted outside a clinical trial.

Carboplatin and vinorelbine in the treatment of advanced non-small-cell lung cancer: a multicenter phase II study.

The aim of this study was to identify a chemotherapy combination that would be active and well tolerated for palliative treatment of advanced non-small-cell lung cancer (NSCLC). From February 1992 to December 1994, a total of 77 patients affected by stage-IIIB and stage-IV NSCLC were treated with carboplatin 350 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8 of each cycle, with cycles repeated every 28 days. All patients were evaluable for response and toxicity. A total of 24 patients showed a partial response (31% response rate; 95% CI = 21-41%). The median duration of overall survival was 41 weeks (95% CI = 31-51), and the median time to disease progression was 34 weeks (95% CI = 25-43). The treatment was well tolerated: no grade-4 toxicity was observed. The carboplatin-vinorelbine combination deserves to considered as a valid alternative to regimens that include cisplatin for palliative treatment of advanced NSCLC.

Combination chemotherapy with epirubicin and mitomycin C as first-line treatment in advanced breast cancer.

From December 1988 to February 1991, 112 consecutive patients were submitted to epirubicin + mitomycin C chemotherapy as first-line treatment for advanced breast cancer. Epirubicin (75 mg/m2) was given every 3 weeks and mitomycin C (10 mg/m2) every 6 weeks. Only patients with visceral involvement or with a disease-free interval of less than 12 months were considered eligible. 102 patients were evaluated for response and toxicity in the present analysis. The main sites of involvement were viscera, soft tissues, bone in 71 (69.6%), 19 (18.6%) and 12 (11.8%) patients, respectively. Multiple site involvement was present in 66 (64.7%) cases. A total of 726 courses of therapy were administered (range 2-14; mean 7.2). Follow-up ranged from 96 to 210 weeks (median follow-up 138 weeks). Response rate was complete response (CR): 21.6% [95% confidence interval (CI) +/- 0.8], partial response (PR) 49.0% (95% CI +/- 0.1), stable disease (SD) 12.7% (95% CI +/- 0.1), progressive disease (PD) 16.7% (95% CI +/- 0.1), CR + PR: 70.6% (95% CI +/- 0.1). Median values of survival and time to progression were 79.4 and 42 weeks, respectively. At 2 years, 37.2 +/- 4.7% and 12.8 +/- 3.3% of the patients, respectively, were alive or without evidence of progression. Toxicity was generally mild. One hundred and four (14.3%) cycles in 53 patients were delayed due to haematological (82) or cardiac (3) toxicity, infectious disease (11) or causes not related to the treatment (8).

Conventional versus high-dose epidoxorubicin as single agent in advanced breast cancer.

Between March 1986 and December 1987, two groups of consecutive patients with advanced breast cancer underwent epidoxorubicin (Epidx) monochemotherapy. Twenty-three patients (group A) received Epidx at a dose of 60 mg/m2 and 27 (group B) at a dose of 120 mg/m2 (i.v. every 3 weeks). No patient had undergone anthracycline treatment before entering the study. Age ranged from 39 to 70 years (mean 52) in group A and from 35 to 69 (mean 50 in group B). The main sites of involvement were liver (5 patients in group A and 10 in group B), lung (4 and 5 patients, respectively), bone (7 and 8 patients, respectively), and soft tissue (6 and 5 patients, respectively). The number of courses of therapy ranged from 4 to 10 (mean 7.4) in group A and from 3 to 10 (mean 6.6) in group B. Tumor response and toxic effects were graded according to World Health Organization criteria. CR + PR were 35% in group A and 67% in group B (chi square = 3.862, p < 0.05). Results were analyzed at 130 weeks from the beginning of the therapy. At this time, survival was 9% in group A and 15% in group B, with a median survival time of 61 weeks (range 18-130) and 77 weeks (range 24-130), respectively. No patient in group A showed cardiac toxicity higher than grade 2 during or after the treatment, whereas in group B, 2 patients developed congestive heart failure after a cumulative Epidx dose of 1080 and 1200 mg/m2. Treatment delays, to allow recovery of white blood cells, were infrequent and occurred only in patients previously subjected to chemotherapy. No patient required hospitalization for sepsis, and alopecia was reversible in all patients. Our data demonstrate that there is a relationship between Epidx dose and response rate in advanced breast cancer.