Citations

Purpose Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown. Methods We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling. Results Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes. Conclusion In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.

Purpose To compare magnetic resonance imaging (MRI) and computed tomography (CT) with each other and to International Federation of Gynecology and Obstetrics (FIGO) clinical staging in the pretreatment evaluation of early invasive cervical cancer, using surgicopathologic findings as the reference standard. Patients and Methods This prospective multicenter clinical study was conducted by the American College of Radiology Imaging Network and the Gynecologic Oncology Group from March 2000 to November 2002; 25 United States health centers enrolled 208 consecutive patients with biopsy-confirmed cervical cancer of FIGO stage ≥ IB who were scheduled for surgery based on clinical assessment. Patients underwent FIGO clinical staging, helical CT, and MRI. Surgicopathologic findings constituted the reference standard for statistical analysis. Results Complete data were available for 172 patients; surgicopathologic findings were consistent with FIGO stages IA to IIA in 76% and stage ≥ IIB in 21%. For the detection of advanced stage (≥ IIB), sensitivity was poor for FIGO clinical staging (29%), CT (42%), and MRI (53%); specificity was 99% for FIGO clinical staging, 82% for CT, and 74% for MRI; and negative predictive value was 84% for FIGO clinical staging, 84% for CT, and 85% for MRI. MRI (area under the receiver operating characteristic curve [AUC], 0.88) was significantly better than CT (AUC, 0.73) for detecting cervical tumors (P = .014). For 85% of patients, FIGO clinical staging forms were submitted after MRI and/or CT was performed. Conclusion CT and MRI performed similarly; both had lower staging accuracy than in prior single-institution studies. Accuracy of FIGO clinical staging was higher than previously reported. The temporal data suggest that FIGO clinical staging was influenced by CT and MRI findings.

Purpose To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) when administered as a 1-hour infusion over 3 consecutive days to children with recurrent or refractory solid tumors. Patients and Methods Flavopiridol was administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days, or when hematologic toxicity or any grade 2 or greater nonhematologic toxicity resolved. The starting dose was 37.5 mg/m2/d. Dose escalation was in cohorts of three patients in a standard fashion until dose-limiting toxicity and the maximum-tolerated dose were determined. Flavopiridol levels were measured on days 1, 2, and 3. Results Twenty-five children received flavopiridol at doses of 37.5 to 80 mg/m2/day over 3 consecutive days. The maximum-tolerated dose was 62.5 mg/m2/d. The primary dose-limiting toxicities were neutropenia and diarrhea. No antitumor effect was observed in this population. Mean peak plasma concentrations of 3.71 and 9.11 μmol/L were achieved at the end of the 1-hour infusion, following dose escalation from 37.5 mg/m2 to 80 mg/m2, respectively. The median flavopiridol plasma clearance was 8.0 L/h/m2 (range, 2.6 to 17.1 L/h/m2). Conclusion The maximum-tolerated dose of flavopiridol in children, and the recommended phase II dose for pediatric studies, was 62.5 mg/m2/day when administered as a 1-hour infusion for 3 consecutive days. Dose-limiting toxicities of neutropenia and diarrhea were similar to those in adult studies.

Purpose Adverse events (AEs) are monitored in clinical trials for patient safety, to satisfy reporting requirements, and develop safety profiles. Recently, much attention has been placed on the reporting of serious AEs (SAEs) that are either life threatening or lethal in clinical trials. However, SAEs comprise a small subset of all AE data collected for trials; the majority of AE data collected are routine AEs (RAEs) regarding non–life-threatening events. We assessed the utility of the RAE data collected, relative to the volume. Patients and Methods We surveyed the RAE data from 26 North Central Cancer Treatment Group coordinated trials. Results A total of 8,318 (11%) of 75,598 of RAEs required queries. Of these, 86% were protocol-required RAEs, 83% of RAEs required per protocol were within normal limits (eg, platelets) or not present, and 61% of extra AEs were mild. One fifth of RAEs were considered unlikely to be related or unrelated to treatment. Overall, 3% of events were severe, life threatening, or caused death. Only 1% of RAE data reported required expedited reporting (eg, via Adverse Event Expedited Reporting System). Results indicate that 72% of RAEs would be eliminated if only the maximum severity per patient and type were required. These results were validated in a large phase III trial. Conclusion The majority of RAEs identified, transcribed, and entered are not clinically important. Our data suggest that reducing the number of AEs monitored will affect substantially neither overall patient safety nor compromise evaluation of regimens undergoing testing. We present several considerations for such a reduction in data collection, as well as a policy that we have used to address the deluge of RAE data.

Purpose To answer the question, “should elderly non–small-cell lung cancer patients be offered elderly-specific trials?” Patients and Methods The North Central Cancer Treatment Group (NCCTG) performed a pooled analysis of elderly patients who participated in elderly-specific trials (required age ≥ 65 years) and age-unspecified trials (required age ≥ 18 years). Between 1998 and 2000, all NCCTG non–small-cell lung cancer (NSCLC) patients with incurable cancer, age ≥ 65 years, and receiving first-line chemotherapy were included. A total of 118 elderly patients participated in elderly-specific trials, and 108, in age-unspecified trials. Demographics and outcomes were compared based on trial type. Results The median age of elderly patients in elderly-specific trials was greater: median (range): 73 years (65 to 87) and 70 years (65 to 85), respectively (P < .001), as was the percentage older than 80 years: 17% and 3%, respectively (P = .0008). Median survival times were 232 and 302 days, respectively (P = .08). After adjustment for baseline age, Eastern Cooperative Oncology Group performance score, cancer stage, and body mass index, this survival difference was not statistically significant (hazard ratio = 1.25; P = .16). Grade 3 or worse nonhematologic adverse event rates were greater in age-unspecified trials (81% v 57%, respectively; P < .001), as were grade 3 or worse hematologic events (68% v 10%, respectively; P < .001). Conclusion Elderly patients in NSCLC elderly-specific trials suffered lower rates of severe adverse events with no statistically significant differences in survival. It seems that elderly-specific trials are providing quality care and helping to define optimal cancer therapy in the elderly, particularly among the “oldest of the old.”

AbstractB-lymphocyte homeostasis and function are regulated by complementary actions of the TNFR family members TACI, BCMA, and BAFF-R, which are expressed by mature B cells. How these receptors are differentially activated is not entirely understood, because the primary ligand BAFF binds to all three. We searched for alternative ligands for TACI using recombinant TACI-Fc fusion protein as a probe and identified syndecan-2 as a new binding partner. TACI binding appears to require heparan sulfate posttranslational modifications of syndecan-2, because free heparin or pretreatment with heparitinase blocked the interaction. Syndecan-2 bound TACI but bound neither BAFF-R nor BCMA. Transfected cells expressing syndecan-2 activated signaling through TACI, as indicated by an NFAT-specific reporter. Syndecan-1 and syndecan-4 were also able to induce TACI signaling in a similar manner. This is the first identification of ligands that selectively activate TACI without simultaneously triggering BCMA or BAFF-R. This finding may help explain the alternative outcomes of signaling from this family of receptors in B cells.