A dose-finding study of miltefosine (hexadecylphosphocholine) in patients with metastatic solid tumours

The ether lipid miltefosine (hexadecylphosphocholine) was orally given to patients with various tumours in a dose-finding study. All patients initially received a daily total dose of 100 mg, which in the absence of side-effects was increased to 150 mg and further to 200 mg. A total of 54 patients were entered and were evaluable for gastrointestinal toxicity. Nausea and vomiting were found to be dose-limiting; 22% of patients ultimately tolerated a dose of 100 mg, 59% tolerated a dose of 150 mg and 19% tolerated a dose of 200 mg. In addition 30% of patients developed renal dysfunction, which was thought to be related to the drug. No other toxities were observed. For further phase II studies it is recommended that one starts with a dose of 150 mg daily, divided over three administrations

The course of neuropathy after cessation of cisplatin treatment, combined with Org 2766 or placebo

Peripheral neuropathy is an important and disabling side-effect of cisplatin treatment. A new drug, Org 2766, has been found to prevent this neuropathy up to 1 month after treatment. A group of 18 patients with ovarian cancer, who participated in an earlier randomized study with placebo or Org 2766, together with cisplatin and cyclophophamide, were thereafter prospectively followed up to 2 years after discontinuation of treatment to monitor the development of neurological signs and symptoms and vibration perception threshold (VPT). Exploratory, descriptive data analysis shows that between 1 and 4 months after the last cycle the average sum score for neurological signs and symptoms and VPT had deteriorated compared with 1 month after treatment. Thereafter a gradual but incomplete improvement was seen between 4-12 and 12-24 months after treatment. These changes were seen in all patients regardless of previous treatment with Org 2766 or placebo, but deterioration was less pronounced in patients previously treated with Org 2766. These results suggests that treatment with Org 2766 to prevent a cisplatin-induced neuropathy should possibly be continued up to 4 months after the last cycle of cisplatin

Effect of an ACTH(4-9) analogue on cisplatin neuropathy of longstanding duration: A phase II study

The efficacy of Org 2766, an ACTH(4–9) analogue, on the recovery of cisplatin neuropathy of longstanding duration was investigated in a phase II study. Twenty-two patients were treated with Org 2766 during a period of 4 months and vibration perception threshold (VPT) and sum scores for neuropathic symptoms and signs were compared with pre-treatment values. No change in VPT could be detected. Although there was a small improvement of clinical measures for neuropathy, no clear evidence for repair could be obtained. These results indicate no beneficial effect of Org 2766 on recovery of a longstanding cisplatin neuropathy

The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel

This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 +/- 7.78 liters/h/m2 and 23.4 +/- 4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics

Phase II study of neo-adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus

BACKGROUND: We have previously reported a favourable response rate in patients with advanced esophageal cancer after treatment with a biweekly regimen of paclitaxel and cisplatin. In this study we investigate the feasibility and efficacy of this regimen in a neo-adjuvant setting. PATIENTS AND METHODS: Patients with resectable squamous cell carcinoma of the esophagus received paclit-axel 180 mg/m(2) and cisplatin 60 mg/m(2) every 2 weeks. Patients received three courses and responding patients received three additional courses; thereafter, patients were referred for surgery. Patient characteristics of 50 eligible patients were as follows: male, 60%; median age, 62 years (range 45-78); median World Health Organization performance status of 1 (range 0-2). RESULTS: Ninety-four per cent of patients received at least three courses of chemotherapy. Haematological toxicity consisted of National Cancer Institute-Common Toxicity Criteria grade 3 or 4 neutropenia in 71% of patients, with neutropenic fever occurring in only two patients (4%). The overall response rate was 59%. Pathological examination showed tumour-free margins in 38 patients. In seven patients no residual tumour was found. The median overall survival was 20 months and the 1- and 3-year survival rates were 68% and 30%, respectively. CONCLUSIONS: This dose-dense schedule of paclitaxel and cisplatin administered biweekly is well tolerated and the observed overall and complete response rates are promising

Mismatch repair and treatment resistance in ovarian cancer

BACKGROUND: The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. METHODS: We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines RESULTS: MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. CONCLUSION: No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation

A phase II study of weekly high-dose cisplatin combined with oral etoposide in advanced non-small-cell lung cancer

As a dose-response relationship has been suggested for cisplatin, it appeared attractive to explore high-dose-intensity regimens in non-small-cell lung cancer. In a phase I study of weekly administration of cisplatin combined with oral etoposide we achieved a cisplatin dose intensity of 52.5-60 mg/m2 per week in most patients. We subsequently explored this regimen in advanced non-small-cell lung cancer. Patients were treated with cisplatin infused at 70 mg/m2 on days 1, 8, 15 and 29, 36, 43 in combination with oral etoposide given at 50 mg on days 1-15 and 29-43. Patients showing stable disease or a better response were continued on treatment with oral etoposide given at 50 mg/m2 per day on days 1-21 every 28 days for a maximum of four cycles. In all, 22 patients with stage III disease and 31 patients with stage IV disease entered the study. The median number of cisplatin administration was 6 per patient; 17 patients reached the planned cisplatin dose intensity of 60 mg/m2 per week, 11 patients achieved 52.5 mg/m2 per week, and 7 patients reached 47 mg/m2 per week. Overall, 11 of 21 stage III patients had a partial response [response rate 51%, 95% confidence interval (CI) 36-81%], as did 9 of 28 patients with stage IV disease (32%; 95% CI 15-49%). Toxicity was mainly hematologic, with leukocytopenia being the most frequent cause of treatment delay. Nephrotoxicity of grade 1 was observed in seven patients. Two patients developed clinical hearing loss. With this schedule a high median cisplatin dose intensity of 52.5-60 mg/m2 per week was reached. The 51% response rate achieved in stage III disease makes this schedule attractive for further exploration; however, it is not recommended for routine use in stage IV disease

Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in metastatic malignant melanoma

The results of cytostatic therapy in metastatic melanoma are very disappointing. In phase II studies with high-dose cisplatin regimens, a remarkably high response rate was observed. In a phase I study with a short course of weekly cisplatin, combined with oral etoposide, we were able to reach, in most patients, a cisplatin dose intensity of 60 mg/m2/week. We performed a phase II study with this schedule in metastatic malignant melanoma. 15 consecutive patients were entered in the study. Treatment consisted of cisplatin 70 mg/m2 on days 1, 8, 15 and days 29, 36, 43 combined with oral etoposide 50 mg daily, days 1-15 and days 29-43. Patients with a response or stable disease continued treatment with oral etoposide 50 mg/m2 daily, days 1-21 every 4 weeks. All patients were evaluable for response and toxicity. The majority of the patients received six cycles of cisplatin with the planned cisplatin dose intensity of 60 mg/m2/week. A partial response was observed in 2 patients (13%; 95% confidence interval (CI) 2-44%) of, respectively, 22 and 12 weeks; stable disease was observed in 6 patients. Toxicity consisted mainly of alopecia and bone marrow suppression. 4 patients had tinnitus, one patient had neurotoxicity grade 1. The regimen studied has only limited activity in metastatic melanoma in spite of the high-dose intensity of cisplatin reached with this schedule

Weekly high-dose cisplatin is a feasible treatment option: Analysis on prognostic factors for toxicity in 400 patients

In the present study we describe the toxicity of weekly high-dose (70-85 mg m-2) cisplatin in 400 patients (203 men, 197 women; median age 54 years) with advanced solid tumours treated in the period 1990-2001 who took part in phase I/II trials, investigating the feasibility and efficacy of weekly cisplatin alone, or in combination with paclitaxel or etoposide. Cisplatin was administered in 250 ml NaCl 3% over 3 h, for six intended administrations. The mean number of administrations was 53 (range, 1-6 administrations). Reasons not to complete six cycles were disease progression (7.5%), haematological toxicity (9%), nephrotoxicity (7%), ototoxicity (2.5%), neurotoxicity (1%), gastrointestinal toxicity (1%), cardiovascular complications (0.5%) or a combination of reasons including noncompliance and patient's request (5.5%). Logistic regression analysis was used to evaluate baseline parameters for prognostic value regarding toxicity. Leukopenia correlated with etoposide cotreatment, and thrombocytopenia with cisplatin dose and prior (platinum-based) chemotherapy. Risk factors for nephrotoxicity were older age, female gender, smoking, hypoalbuminaemia and paclitaxel coadministration. Neurotoxicity >grade I (11% of patients) was associated with prior chemotherapy and paclitaxel coadministration. Symptomatic hearing loss occurred in 15% with anaemia as the predisposing factor. We conclude that weekly high-dose cisplatin administered in hypertonic saline is a feasible treatment regimen