Risks and benefits of phase 1 oncology trials, 1991 through 2002.

BACKGROUND: Previous reviews of phase 1 oncology trials reported a rate of response to treatment of 4 to 6 percent and a toxicity-related death rate of 0.5 percent. These results may not reflect the rates in current phase 1 oncology trials. METHODS: We reviewed all nonpediatric phase 1 oncology trials sponsored by the Cancer Therapy Evaluation Program at the National Cancer Institute between 1991 and 2002. We report the rates of response to treatment, of stable disease, of grade 4 toxic events, and of treatment-related deaths. RESULTS: We analyzed 460 trials involving 11,935 participants, all of whom were assessed for toxicity and 10,402 of whom were assessed for a response to therapy. The overall response rate (i.e., for both complete and partial responses) was 10.6 percent, with considerable variation among trials. "Classic" phase 1 trials of single investigational chemotherapeutic agents represented only 20 percent of the trials and had a response rate of 4.4 percent. Studies that included at least one anticancer agent approved by the Food and Drug Administration constituted 46.3 percent of the trials and had a response rate of 17.8. An additional 34.1 percent of participants had stable disease or a less-than-partial response. The overall rate of death due to toxic events was 0.49 percent. Of 3465 participants for whom data on patient-specific grade 4 toxic events were available, 14.3 percent had had at least one episode of grade 4 toxic events. CONCLUSIONS: Overall response rates among phase 1 oncology trials are higher than previously reported, although they have not changed for classic phase 1 trials, and toxicity-related death rates have remained stable. Rates of response and toxicity vary, however, among the various types of phase 1 oncology trials.

Biological monitoring for selected herbicide biomarkers in the urine of exposed custom applicators: application of mixed-effect models.

Metabolites and/or parent compounds of the herbicides atrazine, alachlor, metolachlor, cyanazine and the 2-ethylhexyl ester of 2,4-dichlorophenoxyacetic acid (2,4-D) were measured in the urine of 15 custom applicators who each provided from five to seven 24 h urine samples during a 6 week period (n = 87). Each applicator provided a pre-season urine sample and a reference population (n = 46) provided first-morning urine samples. Urinary biomarkers were measured by either immunoassay or gas chromatography. During the spraying season, the geometric mean amount of alachlor mercapturate equivalents (eq.), atrazine eq., 2,4-D and metolachlor mercapturate eq. excreted in 24 h was 17, 19, 110 and 22 nmol, respectively. Mixed-effect models were used to determine predictors of the amount of atrazine eq. and 2,4-D excreted in 24 h. The specific days of herbicide spraying associated with increased biomarker excretion varied for the two analytes, and included one or more days prior to urine collection. This confirms the importance of collecting covariate information on day(s) most relevant to the biomarker of interest. The within-worker variance component, expressed as a geometric standard deviation ((W)GSD range: 2.5-2.9), was substantially larger than the between-worker component ((B)GSD range: 1.3-1.5) for the modeled biomarkers. Alachlor mercapturate eq. and metolachlor mercapturate eq. were detected in more than half of the applicator pre-season urine samples. All biomarkers were detected infrequently in the reference population. Evaluation of non-spray exposure determinants was limited by inclusion of prior day spraying, adjustment for time and the small sample size.