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Idoxifene is a novel selective oestrogen receptor modulator (SERM) which had greater binding affinity for the oestrogen receptor (ER) and reduced agonist activity compared with tamoxifen in preclinical studies. In a randomized phase II trial in 56 postmenopausal patients with progressive locally advanced/metastatic breast cancer we assessed whether idoxifene showed evidence of activity compared with an increased 40 mg/day dose of tamoxifen in patients who had previously demonstrated resistance to the standard 20 mg/day dose of tamoxifen. Of 47 patients eligible for response (25 idoxifene, 22 tamoxifen), two partial responses and two disease stabilizations (SD) for >6 months were seen with idoxifene (overall clinical benefit rate 16%, 95% CI 4.5-36.1%). The median duration of clinical benefit was 9.8 months. In contrast, no objective responses were seen with the increased 40 mg/day dose of tamoxifen, although two patients had SD for 7 and 14 months (clinical benefit rate 9%, 95% CI 1.1-29.2%). Idoxifene was well tolerated and the reported possible drug-related toxicities were similar in frequency to those with tamoxifen (hot flushes 13% vs 15%, mild nausea 20% vs 15%). Endocrine and lipid analysis in both groups showed a similar significant fall in serum follicle-stimulating hormone and luteinizing hormone after 4 weeks, together with a significant rise in sex hormone binding globulin levels and 11% reduction in serum cholesterol levels. In conclusion, while idoxifene was associated with only modest evidence of clinical activity in patients with tamoxifen-resistant breast cancer, its toxicity profile and effects on endocrine/lipid parameters were similar to those of tamoxifen.

The protein binding of etoposide was studied in vivo in 36 cancer patients receiving etoposide therapy. Free etoposide was separated from plasma using an ultrafiltration method and the etoposide concentrations (free and total) were measured by high-performance liquid chromatography (HPLC). Considerable interpatient variation in the protein binding of etoposide was observed. The protein binding of etoposide varied from 80% to 97% (mean, 93%). Univariate analysis showed a significant inverse correlation between the free fraction of etoposide and serum albumin (r = 0.74), daily dose (r = 0.37) and age (r = -0.34). Multivariate analysis demonstrated that serum albumin and age were independent predictors of the etoposide free fraction. Serum bilirubin showed no correlation with etoposide protein binding. There is wide variation in etoposide protein binding in cancer patients, which is mostly dependent on serum albumin concentration.

We report on two patients with non-Hodgkin's lymphoma (NHL) who developed reversible, short-lived neurological deficit following intrathecal (i.t.) chemotherapy. One patient received i.t. methotrexate for treatment of meningeal disease, and the other received i.t. methotrexate with cytosine arabinoside (ara-C) and hydrocortisone as central nervous system (CNS) prophylaxis. Although transient paresis following i.t. chemotherapy has previously been reported, it has been attributed to the preservatives contained in the diluents. Our two patients, however, received preservative-free solutions.

Chemotherapy with mitomycin C, ifosfamide and cisplatin (MIC) is reported to produce responses of 56% and 69% in inoperable non-small-cell lung cancer (NSCLC). We evaluated the regimen in 45 similar patients who received up to six courses of 6 mg/m2 mitomycin C, 3 g/m2 ifosfamide, and 50 mg/m2 cisplatin every 3 weeks. In all, 18 patients had limited disease (LD) and 27 had extensive disease (ED). A total of 18 patients responded (40%), 9/18 with LD and 9/27 with ED; there were 4 complete responders. The median duration of response was 25 weeks, and median survival was 32 weeks (range, 2-96 weeks). Toxicity was moderate. Nausea and vomiting were controlled with i.v. dexamethasone and high-dose metoclopramide. Other toxicities included myelosuppression and alopecia. This study confirms that MIC is one of the most active regimens for treatment of NSCLC, with acceptable toxicity.

Since 1980, 75 patients with small-cell lung cancer (SCLC) have been entered into four consecutive studies of high-dose chemotherapy using autologous bone marrow transplantation (ABMT) to assist haematological recovery. In the first study, 25 patients were treated with cyclophosphamide (160-200 mg/kg) as the sole chemotherapy; in the second (26 patients), the cycle of high-dose cyclophosphamide (with or without 800-1,200 mg/m2 etoposide) was repeated as induction treatment. In the first study, response was high [14 complete responses (CR), 7 partial responses (PR)] but was not increased by repeating the cycle (15 CR, 8 PR), and survival was slightly worse in the second trial. In the third study, 15 patients were treated with doxorubicin, vincristine and etoposide for two cycles and then with 200 mg/kg cyclophosphamide. Although high-dose cyclophosphamide increased the complete response rate, the additional responses were short-lived. In the final study, an attempt was made to increase the initial CR rate by combination chemotherapy using carboplatin (400-600 mg/m2), etoposide (120 mg/m2 x 4) and either high-dose cyclophosphamide (40 mg/kg x 4) or melphalan (140 mg/m2). Although all nine patients responded, none underwent a CR. The long-term survival (up to 7 years) does not appear to be different from that in comparably selected cases treated with conventional chemotherapy.