Secondary analyses of the randomized phase III Stop&Go study: efficacy of second-line intermittent versus continuous chemotherapy in HER2-negative advanced breast cancer

Background: Previously, we showed that reintroduction of the same (first-line) chemotherapy at progression could only partially make up for the loss in efficacy as compared to continuously delivered first-line chemotherapy. Here, we report the probability of starting second-line study chemotherapy in the Stop&Go trial, and the progression-free survival (PFS) and overall survival (OS) of patients who received both the first- and second-line treatment in an intermittent versus continuous schedule. Methods: First-line chemotherapy comprised paclitaxel plus bevacizumab, second-line capecitabine or non-pegylated liposomal doxorubicin, given per treatment line as two times four cycles (intermittent) or as eight consecutive cycles (continuous). Results: Of the 420 patients who started first-line treatment within the Stop&Go trial (210:210), a total of 270 patients continued on second-line study treatment (64% of all), which consisted of capecitabine in 201 patients and of non-pegylated liposomal doxorubicin in 69 patients, evenly distributed between the treatment arms. Median PFS was 3.7 versus 5.0 months (HR 1.07; 95% CI: 0.82–1.38) and median OS 10.9 versus 12.4 months (HR 1.27; 95% CI: 0.98–1.66) for intermittent versus continuous second

The influence on quality of life of intermittent scheduling in first- and second-line chemotherapy of patients with HER2-negative advanced breast cancer

Background: The Stop&Go study randomized patients with advanced breast cancer to intermittent (two times four) or continuous (eight subsequent cycles) first- and second-line chemotherapy. Methods: QoL was measured with RAND-36 questionnaires every 12 weeks. The primary objective was to estimate differences in changes from baseline between intermittent and continuous treatment. An effect size of 0.5 SD (5 points) was considered clinically meaningful. Results: A total of 398 patients were included with a median follow-up of 11.4 months (IQR 5.6–22.2). Mean physical QoL baseline scores were 38.0 resp. 38.2, and mental scores 45.0 resp. 42.4 for intermittent and continuous treatm

A phase I and pharmacological study with imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a novel ruthenium anticancer agent

Purpose: NAMI-A {H2Im[trans-RuCl4(DMSO)HIm] or imidazolium-trans-DMSO-imidazole-tetrachlororuthenate} is a novel ruthenium-containing compound that has demonstrated antimetastatic activity in preclinical studies. This Phase I study was designed to determine the maximum-tolerated dose (MTD), profile of adverse events, and dose-limiting toxicity of NAMI-A in patients with solid tumors. Furthermore, the ruthenium pharmacokinetics (PK) after NAMI-A administration and preliminary antitumor activity were evaluated. Patients and Methods: Adult patients with solid tumors received NAMI-A as an i.v. infusion over 3 h daily for 5 days every 3 weeks. PK of total and unbound ruthenium was determined during the first and second treatment using noncompartmental pharmacokinetic analysis. The total accumulation of ruthenium in WBCs was also quantified. Results: Twenty-four patients were treated at 12 dose levels (2.4-500 mg/m2/day). At 400 mg/m2/day, blisters developed on the hands, fingers, and toes. At 500 mg/m2/day, blisters persisted from weeks to months and slowly regressed. Although no formal common toxicity criteria (CTC) grade 3 developed, painful blister formation was considered dose limiting. Because the first signs developed at 400 mg/m2/day, the advised dose for further testing of NAMI-A was determined to be 300 mg/m2/day on this schedule. PK analysis revealed a linear relationship between dose and area under the concentration-time curve (AUC) of total and unbound ruthenium (R2 = 0.75 and 0.96, respectively) over the whole dose range. Plasma clearance of total ruthenium was 0.17 ± 0.09 liter/h, and terminal half-life was 50 ± 19 h. The volume of distribution at steady state of total ruthenium was 10.1 ± 2.8 liters. The accumulation of ruthenium in WBC was not directly proportional to the increasing total exposure to ruthenium. One patient with pretreated and progressive nonsmall cell lung cancer had stable disease for 21 weeks. Conclusion: NAMI-A can be administered safely as a 3-h i.v. infusion at a dose of 300 mg/m2/day for 5 days, every 3 weeks

Phase I clinical and pharmacologic study of a 2-weekly administration of cisplatin and gemcitabine in patients with advanced non-small cell lung cancer

Our objective was to study the feasibility of schedule- and dose-intensive cisplatin plus gemcitabine in patients with non-small cell lung cancer (NSCLC) when given on 1 day in four 2-weekly cycles. Cisplatin was administered as a 3 h i.v. infusion followed by gemcitabine as a 30-min i.v. infusion on the same day, every 2 weeks. An interval of 1 h between the two infusions was applied. Patients received four courses without any break. An interpatient dose-escalation scheme was used. The starting dose was 87.5 mg/m2 of cisplatin and 1350 mg/m2 of gemcitabine. The pharmacokinetics of cisplatin and gemcitabine were determined in plasma and white blood cells. In total, 23 patients were included in the study. Median age of the patients was 56 years (range 27-76) and most patients were in good clinical condition. Thirteen patients received all planned courses. Dose-limiting toxicity was Common Toxicity Criteria grade 2 ototoxicity. The maximum tolerated dose was established at cisplatin 90 mg/m2 in combination with gemcitabine 1500 mg/m2. This short induction schedule is practical and convenient for the patient. We conclude that the combination of cisplatin at a dose intensity of 51 mg/m2/week followed by gemcitabine (1500 mg/m 2) on the same day is clinically feasible in NSCLC patients when given as a 2-weekly cycle

Relationship between cisplatin administration and the development of ototoxicity

PURPOSE: To determine the auditory toxicity associated with dose- and schedule- intensive cisplatin/gemcitabine chemotherapy in non-small-cell lung carcinoma patients. PATIENTS AND METHODS: Patients were treated with gemcitabine followed by cisplatin according to an interpatient dose-escalation scheme. Patients were randomly assigned to receive treatment once a week for 6 weeks or once every 2 weeks for 4 weeks. The following cohorts of patients were treated with a reversed schedule once every 2 weeks, in which cisplatin was followed by gemcitabine. The dose-intensity of cisplatin was equal in both schedules. Audiometric evaluations were obtained for each ear at several frequencies. Mean hearing loss after cisplatin treatment was computed for each dose level at each tested frequency in each ear at baseline and subsequent follow-up audiometry. Pure tone averages (PTAs) were also calculated. The pharmacokinetics of cisplatin was determined to study the correlation among the maximum drug concentration, the area under the curve of unbound platinum, and the development of ototoxicity. RESULTS: A total of 328 audiograms were analyzed. At the higher frequencies, a more severe hearing impairment was recorded. Most patients showed a decrease in hearing thresholds at dosages above 60 mg/m2 cisplatin at the higher frequencies. PTAs at 1, 2, and 4 kHz show a mean hearing loss of 19 dB after cisplatin administration at dosages above 90 mg/m2. Threshold shifts at 8 and 12.5 kHz after cisplatin administration were experienced at dosages above 60 mg/m2. CONCLUSION: Hearing loss after cisplatin therapy occurs mainly at high frequencies and at cisplatin dosages more than 60 mg/m2. It is more pronounced when cisplatin is given once every 2 week

Phase I clinical and pharmacokinetic study of kahalalide F in patients with advanced androgen refractory prostate cancer

The purpose is to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of Kahalalide F (KF) in patients with androgen refractory prostate cancer. Furthermore, the pharmacokinetics after KF administration and preliminary antitumor activity were evaluated. KF is a dehydroaminobutyric acid-containing peptide isolated from the marine herbivorous mollusk, Elysia rufescens. Adult patients with advanced or metastatic androgen refractory prostate cancer received KF as an i.v. infusion over 1 hour, during five consecutive days every 3 weeks. The starting dose was 20 microg per m(2) per day. Clinical pharmacokinetics studies were done in all patients using noncompartmental analysis. Prostate-specific antigen levels were evaluated as a surrogate marker for activity against prostate cancer. Thirty-two patients were treated at nine dose levels (20-930 microg per m(2) per day). The maximum tolerated dose on this schedule was 930 microg per m(2) per day. The dose-limiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose for phase II studies is 560 microg per m(2) per day. Pharmacokinetics analysis revealed dose linearity up to the recommended dose. Thereafter, a more than proportional increase was observed. Elimination was rapid with a mean (SD) terminal half-life (t(1/2)) of 0.47 hour (0.11 hour). One patient at dose level 80 microg per m(2) per day had a partial response with a prostate-specific antigen decline by at least 50% for > or =4 weeks. Five patients showed stable disease. KF can be given safely as a 1-hour i.v. infusion during five consecutive days at a dose of 560 microg per m(2) per day once every 3 week