Dataset Information

Evaluating Treatment Tolerability in Cancer Clinical Trials using the Toxicity Index.

ABSTRACT: BACKGROUND:The 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 (NSABP-R04) clinical trial as an example. METHODS:NSABP-R04 was a neoadjuvant chemo-radiation trial in stage II-III rectal cancer patients. A 2x2 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 (PIMs), where Pr A < B indicates the probability that higher values of TI were observed for A when compared to B. Baseline age, gender, performance status (PS), body mass index (BMI), surgery type and stage were evaluated as independent risk factors. RESULTS:A total of 4,560 toxicities from 1,558 patients were analyzed. Results from adjusted PIMs indicate that oxaliplatin-containing regimens had statistically significant (p?

SUBMITTER: Gresham G

PROVIDER: S-EPMC7735773 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Evaluating Treatment Tolerability in Cancer Clinical Trials Using the Toxicity Index.

Gresham Gillian G Diniz Márcio A MA Razaee Zahra S ZS Luu Michael M Kim Sungjin S Hays Ron D RD Piantadosi Steven S Tighiouart Mourad M Yothers Greg G Ganz Patricia A PA Rogatko André A

Journal of the National Cancer Institute 20201201 12

<h4>Background</h4>The 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.<h4>Methods</h4>National Surgical Adjuvant Breast and Bowel Project R-04 was ...[more]

PMID: 32091598

Similar Datasets

Project description:ImportanceIn science and medical research, extreme and dichotomous conclusions may be drawn based on whether the P value falls above or below the threshold. The fragility index (ie, the minimum number of changes from nonevents to events resulting in loss of statistical significance) captures the vulnerability of statistics in trials with binary outcomes. There are a growing number of clinical trials of immune checkpoint inhibitors (ICIs), as well as expanding eligibility for patients to receive them. The robustness of survival outcomes in randomized clinical trials (RCTs) should be evaluated using the fragility index extended to time-to-event data.ObjectiveTo calculate the fragility of survival data in RCTs evaluating ICIs.Design, setting, and participantsIn this cross-sectional study, data on phase 3 prospective RCTs investigating ICIs included in PubMed from inception until January 1, 2020, were extracted. Two- or three-group studies reporting results for overall survival were eligible for the survival-inferred fragility index (SIFI) calculation, which is the minimum number of reassignments of the best survivors from the interventional group to the control group resulting in loss of significance (defined as P < .05 by log-rank test). For nonsignificant results, a negative SIFI was calculated by reversing the direction of reassignment (from the control group to the interventional group).Main outcomes and measuresSurvival-inferred fragility index.ResultsA total of 45 phase 3 prospective RCTs (4 of which had 3 groups, for a total of 49 groups) were identified, of which 6 (13%) investigated anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents, 25 (56%) investigated anti-programmed cell death 1 (PD-1) agents, 12 (27%) investigated anti-programmed cell death 1 ligand 1 agents, and 3 (7%) investigated the combination of anti-CTLA-4 and anti-PD-1 agents. The median SIFI was 5 (interquartile range, -4 to 12) for the intention-to-treat analysis; for these trials, the SIFI was 1% or less of the total sample size in 17 of 49 populations (35%). In 25 of the 49 intention-to-treat populations (51%), the SIFI was less than the number of censored patients in the intervention group shortly after randomization (defined as <5% of the follow-up time).Conclusions and relevanceThis study suggests that many phase 3 RCTs evaluating ICI therapies have a low SIFI for overall survival, resulting in uncertainty regarding their potential clinical benefit. Although not a definitive solution for the problems arising from dichotomization, SIFI provides an additional means of assessing and communicating the strength of statistical conclusions.

Project description:ImportanceBiologics account for almost half of US drug spending but may be subject to competitive pricing pressures by US Food and Drug Administration-approved biosimilars. The extent of the preapproval clinical testing that is needed and how these biosimilars compare with the originator biologic products remain critical issues in establishing a vibrant biosimilar market.ObjectivesTo analyze the design of cancer biosimilar efficacy studies compared with the reference drug pivotal trials and provide summary risk ratio estimates for each cancer type drug subgroup.Data sourcesA systematic search was performed of articles and abstracts published using Embase, PubMed/MEDLINE, and ClinicalTrials.gov, last updated April 18, 2021.Study selectionAll studies or abstracts in English comparing a disease-modifying cancer biologic and its biosimilar and reporting efficacy or surrogate efficacy results were included.Data extraction and synthesisOutcome estimates and study characteristics were extracted from each study. Among biosimilar efficacy studies, random-effects meta-analyses were performed for each cancer type molecule outcome subgroup, calculating pooled relative estimates and 95% CIs.Main outcomes and measuresStudy characteristics, such as population size, blinding, and randomization, were compared between biosimilar trials and those of reference drugs. Risk ratio estimates for relative change to surrogate measures (eg, progression-free survival) were collected for biosimilars and their reference products.ResultsA total of 31 cancer biosimilar studies of 3 reference products involving 12 310 patients were included. In all 7 subgroups, the biosimilars analyzed were indistinguishable from their reference drug on surrogate efficacy. Six reference drug trials were included, involving 1811 patients. On average, biosimilar studies involved more patients than reference drug trials (mean number of patients, 397 vs 302), were more likely to be randomized clinical trials rather than single-group or observational studies (100% [31 of 31] vs 50% [3 of 6]), and were more likely to be double blind rather than open label (84% [26 of 31] vs 17% [1 of 6]).Conclusions and relevanceThis systematic review and meta-analysis found that the biosimilars for the cancer drugs in this sample were subjected to rigorous clinical evaluations, and the results were statistically indistinguishable from those of original products across drugs, cancer types, and outcome measures.

Project description:PurposeThe time spent in pursuing treatments for advanced cancer can be substantial. We have previously proposed a pragmatic and patient-centered metric of these time costs-which we term time toxicity-as any day with physical health care system contact. This includes outpatient visits (eg, bloodwork, scans, etc), emergency department visits, and overnight stays in a health care facility. Herein, we sought to assess time toxicity in a completed randomized controlled trial (RCT).MethodsWe conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions versus supportive care alone in 572 patients with advanced colorectal cancer. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1 v 4.6 months). Subsequent analyses reported that benefit was restricted to patients with K-ras wild-type tumors. We calculated patient-level time toxicity by analyzing trial forms. We considered days without health care contact as home days. We compared medians of time measures across arms and stratified results by K-ras status.ResultsIn the overall population, median time toxic days were higher in the cetuximab arm (28 v 10, P < .001) although median home days were not statistically different between arms (140 v 121, P = .09). In patients with K-ras-mutated tumors, cetuximab was associated with almost numerically equal home days (114 days v 112 days, P = .571) and higher time toxicity (23 days v 11 days, P < .001). In patients with K-ras wild-type tumors, cetuximab was associated with more home days (186 v 132, P < .001).ConclusionThis proof-of-concept feasibility study demonstrates that measures of time toxicity can be extracted through secondary analyses of RCTs. In CO.17, despite an overall OS benefit with cetuximab, home days were statistically similar across arms. Such data can supplement traditional survival end points in RCTs. Further work should refine and validate the measure prospectively.[Media: see text].

Project description:BackgroundTo construct an effective prognostic index to predict overall survival (OS) and triplet regimen efficacy for advanced gastric cancer (AGC) patients treated with platinum-based and fluorouracil-based chemotherapy.ObjectivesBetween 2011 and 2021, 679 patients from two randomized phase III trials and one phase II trial were enrolled.DesignsWe collected 11 baseline clinicopathological and 14 hematological parameters to establish a prognostic index.MethodsUnivariate and multivariate Cox analyses were used to screen prognostic factors, and a prognostic index nomogram was conducted.ResultsSeven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic nomogram named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in the low-risk group (median OS, 15.5 versus 8.0 months, p < 0.001). The areas under the curve of the FARS index for 1-, 2-, and 3-year OS were 0.70, 0.72, and 0.77, respectively. A validation and external cohort verified the prognostic value of the FARS index. Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (p = 0.018).ConclusionThe constructed FARS index to predict the OS of AGC patients and the TRIS index to screen out the dominant population for triplet regimens can be used to aid clinical decision-making and individual risk stratification.

Dataset Information

Evaluating Treatment Tolerability in Cancer Clinical Trials using the Toxicity Index.

Publications

Evaluating Treatment Tolerability in Cancer Clinical Trials Using the Toxicity Index.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets