Citations

5554 Background: Epithelial ovarian cancer (EOC) is characterized by chemoresistant recurrences primarily confined to the intraperitoneal cavity, frequently leading to malignant small bowel obstructions. Intraperitoneal (IP) chemotherapy has been incorporated in EOC, but only in the first-line setting. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel IP drug delivery method that optimizes tissue penetration depth and drug distribution, to treat recurrent peritoneal malignancies. Recent trials outside the U.S. demonstrated partial to stable response following PIPAC in recurrent EOC. To date, no clinical trials have been completed investigating the role of PIPAC in EOC in the United States. Methods: We performed a multicenter prospective phase I trial using IP cisplatin 10.5 mg/m2 and doxorubicin 2.1 mg/m2 via PIPAC at 6-week intervals. Patients were eligible if they had recurrent disease with peritoneal metastasis; extraperitoneal metastasis was allowed. The primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included progression free survival, PCI scoring, RECIST measurements, and quality of life (QoL). The patients with gastric and uterine cancers’ toxicity data were used but given inherent prognostic differences the treatment efficacy for these patients were not used in this analysis. Adverse event (AE) monitoring was graded using CTCAE spanning 18 weeks. Following completion of treatment (³2 PIPACs) patients were followed up every 12 weeks. QoL was measured using patient-reported assessments at 0, 6, 12, and 18 weeks. Baseline demographics were summarized. Mean change in PCI was calculated between cycle (C) 1 and 2, and cycle 2 and 3. Toxicities attributed to the surgery or PIPAC were reported with highest grade for each patient. Results: Nine heavily pretreated, recurrent patients were enrolled in the trial: 7 with platinum-resistant recurrent EOC, 1 with uterine cancer, and 1 with gastric cancer. PIPAC completion rate was 71.4%. Median age of participants was 65 years. Median prior lines of chemotherapy were 4 (range 2 - 10). No surgical complications occurred in the cohort. Two patients came off study: one for G3 abdominal pain and the other for G3 anorexia. For the EOC cohort, the median PCI reduction was -1.4% (C1 to C2) and -2.8% (C1 to C3). One low-grade serous EOC patient demonstrated a partial response based on RECIST criteria and received 6 cycles. Two EOC patients showed an initial response based on PCI reduction, but progressed following Cycle 2. Overall, QoL was stable. Conclusions: PIPAC with cisplatin/doxorubicin in platinum-resistant ovarian cancer is well tolerated. Intraperitoneal responses were seen in a subset of low-grade serous ovarian cancer patients, which may warrant further study. Heavily pretreated, platinum-resistant high-grade EOC patients derived limited intraperitoneal control from PIPAC monotherapy. Clinical trial information: NCT04329494 .

Abstract Context. —In proficiency testing surveys, there are differences in the values reported by users of various analytic methods. Two contributors to this variation are calibrator bias and matrix effects of proficiency testing materials. Objectives. —(1) To quantify the biases of the analytic methods used to measure thyroid-stimulating hormone, thyroxine, triiodothyronine, free thyroxine, and free triiodothyronine levels; (2) to determine if these biases are within allowable limits; and (3) to ascertain if proficiency testing materials correctly identify these biases. Design. —A fresh frozen serum specimen was mailed as part of the 2003 College of American Pathologists Ligand and Chemistry surveys. The means and SDs for each analytic method were determined for this sample as well as for a proficiency testing sample from both surveys. In the fresh frozen serum sample, target values for thyroxine and triiodothyronine were determined by isotope dilution/liquid chromatography/tandem mass spectrometry. All other target values in the study were the median of the means obtained for the various analytic methods. Main Outcome Measures. —Calibration biases were calculated by comparing the mean of each analytic method with the appropriate target values. These biases were evaluated against limits based on intra- and interindividual biological variation. Matrix effects of proficiency testing materials were assessed by comparing the rank of highest to lowest analytic method means (Spearman rank test) for each analyte. Participants. —Approximately 3900 clinical laboratories were enrolled in the College of American Pathologists Chemistry and Ligand surveys. Results. —The number of methods in the Ligand Survey that failed to meet the goals for bias was 7 of 17 for thyroid-stimulating hormone and 11 of 13 for free thyroxine. The failure rates were 12 of 16 methods for thyroxine, 8 of 11 for triiodothyronine, and 9 of 11 for free triiodothyronine. The means of the analytic method for the proficiency testing material correlated significantly ( P < .05) only with the fresh frozen serum means for thyroxine and thyroid-stimulating hormone in the Chemistry Survey and free triiodothyronine in the Ligand Survey. Conclusions. —A majority of the methods used in thyroid function testing have biases that limit their clinical utility. Traditional proficiency testing materials do not adequately reflect these biases.

Abstract Context. —The College of American Pathologists (CAP) provides proficiency testing (PT) surveys to laboratories around the world. Objectives. —To compare diagnostic assay methods for serum/plasma cortisol and immunoglobulin (Ig) E in terms of their bias and precision, to determine how well CAP PT specimens simulate human serum, and to reassess proficiency test grading criteria in light of these findings. Design. —A participant-blinded, prospective trial. One vial of pooled fresh frozen serum (FFS) and 4 different admixtures of PT material (PTM) were sent to laboratories participating in PT surveys. Participants. —Laboratories providing cortisol (>1000) or IgE (>230) results among the subscribers to the CAP surveys, Ligand (General) 2003, set K/KN-A and Chemistry 2003, set C-C. Main Outcome Measures. —The main outcome measures were (1) bias among laboratories using the same method (peer groups), defined relative to the median of method means (MedMM); (2) imprecision as measured by the SD and coefficient of variation (CV) about each method mean; and (3) total error across laboratories for the FFS cortisol results, defined as |Bias Relative to Reference Method| + 2 SD. Results. —Cortisol method biases, relative to MedMM, ranged from −22% to 9% for the FFS challenge and from −24% to 36% for comparable PTM challenges. The method biases, relative to the reference method, ranged from −3% to 19% for the FFS challenge. The cortisol method CVs ranged from 4.2% to 13.6% for the FFS challenge and from 4.7% to 12.7% for comparable PTM challenges. Total error across laboratories ranged from 1.4 to 6.9 μg/dL (39 to 190 nmol/L) for the FFS challenge. Immunoglobulin E method biases, relative to MedMM, ranged from −8% to 9% for the FFS challenge and from −7% to 5% for comparable PTM challenges. The IgE method CVs ranged from 3.6% to 6.7% for the FFS challenge and from 3.4% to 9.8% for comparable PTM challenges. Conclusions. —The bias for cortisol results was less with FFS than with PTM, but imprecision was comparable. The FFS MedMM was 8.5% higher than the reference value. Fresh frozen serum and PTM bias and imprecision for IgE methods were each less than 10%. Because some of the methods demonstrated greater bias when analyzing PTM than FFS, peer group grading of both these analytes is appropriate.

Abstract Objective.—To identify the sources of analytical variation for cyclosporine and tacrolimus in a 3-year longitudinal study. Design.—Two pools of whole blood were spiked with cyclosporine and tacrolimus, respectively. One aliquot of cyclosporine and 2 of the tacrolimus pool were distributed in the first and last mailing for years 1999 to 2001. For both drugs, the total variance for each method was partitioned into within- and between-laboratory components. Setting.—The A and C mailings of the 1999, 2000, and 2001 AACC/CAP [American Association for Clinical Chemistry/College of American Pathologists] Immunosuppressive Drugs (CS) Monitoring Survey. Main Outcome Measures.—For each drug, total variance was partitioned into specimen, mailing, year, and interlaboratory effects for each analytical method. Participants.—The 292 laboratories for cyclosporine and 177 laboratories for tacrolimus enrolled in the survey from 1999 to 2001. Results.—For both cyclosporine and tacrolimus, the major source of imprecision came from within-laboratory factors, which accounted for nearly 85% (range, 77% to 90%) of the total variance. For cyclosporine, the major component of within-laboratory variance was between-mailing, within-year effect, whereas for tacrolimus it was the between-year, within-laboratory variation. Conclusion.—The major source of long-term survey imprecision for cyclosporine and tacrolimus is within-laboratory factors. The finding that 85% of the total variance was due to within-laboratory variation is similar to other therapeutic drugs.

Abstract Objective.—To determine if the levels of imprecision of the commonly used analytic methods for drug measurements are suitable for long-term therapeutic drug monitoring. Design.—In 1996, 4 identical lyophilized samples (2 in the first mailing and 2 in the second mailing 4 months later) were sent to laboratories participating in a nationwide proficiency testing program. Similarly, in 1999, replicates from a liquid pool of spiked sera were mailed 3 times, 4 months apart, to participating laboratories. For each of 11 drugs regulated under the Clinical Laboratory Improvement Amendments of 1988 and 1 metabolite, the total variance for each method was partitioned into within- and between-laboratory components. The total within-laboratory and the total survey coefficients of variation (CVs) for each method were then compared with the “acceptable” precision criteria of Glick, Burnett, and Fraser for each drug. Setting.—The first 2 mailings of the College of American Pathologists Therapeutic Drug Monitoring surveys for 1996, sets Z and ZM, and the 3 mailings of 1999, sets ZM, Z, and Z2. Main Outcome Measures.—For each drug studied, the CV of each method was compared with the various imprecision criteria, and if greater than any of the criteria, the method was then tabulated as not meeting that specific criterion. Participants.—The approximately 5000 participants of the survey. Results.—The number of methods deemed as not having acceptable total long-term within-laboratory precision by the various criteria ranged from 35% to 88% in 1996 and from 22% to 77% in 1999. Conclusion.—The number of failures possibly indicates that many of the reagent assays being utilized are not precise enough for long-term therapeutic drug monitoring of chronically administered drugs or that the published criteria used to evaluate the data in this study are too stringent.

Abstract Objective. —To determine the magnitudes and sources of analytic variation in testing for therapeutic drugs. Specifically, among laboratories using the same analytic method, to compare the within-laboratory variation (including both short- and long-term variation) with the between-laboratory variation. Design. —Four identical challenges were prepared from a lyophilized pool of spiked sera and were sent in pairs 4 months apart to laboratories participating in a nationwide proficiency-testing program. For each of 25 drugs, the variability in reported results from laboratories using the same method was investigated using nested analysis of variance. Setting. —The first 2 mailings of the College of American Pathologists Therapeutic Drug Monitoring Survey, 1996, sets Z and ZM. Main Outcome Measures. —For each drug, total variance was partitioned into within- and between-laboratory components for common methods. The within-laboratory component was further partitioned into short- and long-term components. Participants. —The approximately 5000 laboratories enrolled in the survey. Results. —For the 25 drugs, the average percentages of the total variance due to short-term, within-laboratory variance; long-term, within-laboratory variance; between-laboratory variance; and total laboratory variance were 25.0% (range, 8.8–50.6%), 57.8% (35.3–73.7%), 17.3% (5.0–35.4%), and 82.7% (64.6–95.0%), respectively. Conclusion. —For all drugs tested, the within-laboratory component of variance was greater than the between-laboratory component of variance. Within laboratories, the magnitude of the long-term component was generally greater than the magnitude of the short-term component. This information will be helpful in determining the clinical utility of various drug assays and in evaluating the appropriateness of regulations involving therapeutic drug testing.