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Toxicity Attribution in Phase I Trials: Evaluating the Effect of Dose on the Frequency of Related and Unrelated Toxicities.

ABSTRACT: Phase I studies rely on investigators to accurately attribute adverse events as related or unrelated to study drug. This information is ultimately used to help establish a safe dose. Attribution in the phase I setting has not been widely studied and assessing the accuracy of attribution is complicated by the lack of a gold standard. We examined dose-toxicity relationships as a function of attribution and toxicity category to evaluate for evidence of toxicity misattribution.Individual patient records from 38 phase I studies activated between 2000 and 2010 were used. Dose was defined as a percentage of maximum dose administered on each study. Relationships between dose and patient-level toxicity were explored graphically and with logistic regression. All P values were two-sided.11,909 toxicities from 1,156 patients were analyzed. Unrelated toxicity was not associated with dose (P = 0.0920 for grade ? 3, P = 0.4194 for grade ? 1), whereas related toxicity increased with dose (P < 0.0001, both grade ? 3 and ? 1). Similar results were observed across toxicity categories. In the five-tier system, toxicities attributed as "possibly," "probably," or "definitely" related were associated with dose (all P < 0.0001), whereas toxicities attributed as "unlikely" or "unrelated" were not (all P > 0.1).Reassuringly, we did not observe an association between unrelated toxicity rate and dose, an association that could only have been explained by physician misattribution. Our findings also confirmed our expectation that related toxicity rate increases with dose. Our analysis supports simplifying attribution to a two-tier system by collapsing "possibly," "probably," and "definitely" related.

SUBMITTER: Eaton A

PROVIDER: S-EPMC4819316 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Toxicity Attribution in Phase I Trials: Evaluating the Effect of Dose on the Frequency of Related and Unrelated Toxicities.

Eaton Anne A Iasonos Alexia A Gounder Mrinal M MM Pamer Erika G EG Drilon Alexander A Vulih Diana D Smith Gary L GL Ivy S Percy SP Spriggs David R DR Hyman David M DM

Clinical cancer research : an official journal of the American Association for Cancer Research 20150831 3

<h4>Purpose</h4>Phase I studies rely on investigators to accurately attribute adverse events as related or unrelated to study drug. This information is ultimately used to help establish a safe dose. Attribution in the phase I setting has not been widely studied and assessing the accuracy of attribution is complicated by the lack of a gold standard. We examined dose-toxicity relationships as a function of attribution and toxicity category to evaluate for evidence of toxicity misattribution.<h4>Ex ...[more]

PMID: 26324741

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Project description:BackgroundThe National Cancer Institute Moonshot research initiative calls for improvements in the analysis and reporting of treatment toxicity to advise key stakeholders on treatment tolerability and inform regulatory and clinical decision making. This study illustrates alternative approaches to toxicity evaluation using the National Surgical Adjuvant Breast and Bowel Project R-04 clinical trial as an example.MethodsNational Surgical Adjuvant Breast and Bowel Project R-04 was a neoadjuvant chemoradiation trial in stage II-III rectal cancer patients. A 2 x 2 factorial design was used to evaluate whether the addition of oxaliplatin (Oxa) to 5-fluorouracil (5FU) or capecitabine (Cape) with radiation therapy improved local-regional tumor control. The toxicity index (TI), which accounts for the frequency and severity of toxicities, was compared across treatments using multivariable probabilistic index models, where Pr A < B indicates the probability that higher values of TI were observed for A when compared with B. Baseline age, sex, performance status, body mass index, surgery type, and stage were evaluated as independent risk factors.ResultsA total of 4560 toxicities from 1558 patients were analyzed. Results from adjusted probabilistic index models indicate that oxaliplatin-containing regimens had statistically significant (P < .001) probability (Pr) for higher TI compared with regimens without oxaliplatin (Pr 5FU < 5FU + Oxa = 0.619, 95% confidence interval [CI] = 0.560 to 0.674; Pr 5FU < Cape + Oxa = 0.627, 95% CI = 0.568 to 0.682; Pr Cape < 5FU + Oxa = 0.587, 95% 0.527 to 0.644; and Pr Cape < Cape + Oxa = 0.596, 95% 0.536 to 0.653). When compared with other existing toxicity analysis methods, TI provided greater power to detect differences between treatments.ConclusionsThis article uses standard data collected in a cancer clinical trial to introduce descriptive and analytic methods that account for the additional burden of multiple toxicities. These methods may provide a more accurate description of a patient's treatment experience that could lead to individualized dosing for better toxicity control. Future research will evaluate the generalizability of these findings in trials with similar drugs.

Dataset Information

Toxicity Attribution in Phase I Trials: Evaluating the Effect of Dose on the Frequency of Related and Unrelated Toxicities.

Publications

Toxicity Attribution in Phase I Trials: Evaluating the Effect of Dose on the Frequency of Related and Unrelated Toxicities.

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