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Evaluation of the contribution of randomised cancer clinical trials evaluating agents without documented single-agent activity.

ABSTRACT: BACKGROUND:With the development of targeted agents, the approach to combination cancer therapy has evolved to focus on identifying ways in which pathway inhibition by one agent may enhance the activity of other agents. In theory, this implies that under this new paradigm, agents are no longer required to show single-agent activity, as the pathway inhibited by the targeted agent may only have a therapeutic effect when given with other agents. This raises the question of the extent to which anticancer agents without single-agent activity can contribute to effective combination regimens. PATIENTS AND METHODS:We reviewed outcomes of randomised phase 2 combination trials sponsored by the National Cancer Institute Cancer Therapy Evaluation Program that were activated in 2008 to 2017 and noted the single-agent activity of the experimental agents. RESULTS:Fifty-three trials were identified, and 50 had available results: 7 (14%), 15 (30%) and 28 (56%) had experimental agents with single-agent activity classified as active, inactive and indeterminate, respectively. Thirteen per cent (95%?CI=1.7%?to 40.5%) of trials evaluating inactive agents and 11.6% (95% CI=3.9%?to 25.1%) of trials evaluating agents without known single-agent activity (pooled inactive and indeterminate) were positive, compared with 42.9% (95% CI=9.9%?to 81.6%) for agents with single-agent activity. CONCLUSIONS:Incorporating agents without documented single-agent activity into treatment regimens is unlikely to produce meaningful improvements in activity unless there is compelling biological rationale. This finding has important implications for the prioritisation of anticancer agents for combination testing, and for the allocation of clinical trial resources.

SUBMITTER: Foster J

PROVIDER: S-EPMC7597487 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Evaluation of the contribution of randomised cancer clinical trials evaluating agents without documented single-agent activity.

Foster Jared J Freidlin Boris B Korn E L EL Smith Malcolm M

ESMO open 20201001 5

<h4>Background</h4>With the development of targeted agents, the approach to combination cancer therapy has evolved to focus on identifying ways in which pathway inhibition by one agent may enhance the activity of other agents. In theory, this implies that under this new paradigm, agents are no longer required to show single-agent activity, as the pathway inhibited by the targeted agent may only have a therapeutic effect when given with other agents. This raises the question of the extent to whic ...[more]

PMID: 33122353

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Project description:IntroductionPatients with a history of chemotherapy or stem cell transplantation (SCT) and prolonged neutropenia are at risk for hepatic and/or splenic seeding of Candida. In our experience, hepatosplenic candidiasis (HSC) without documented candidemia often remains unrecognized.Case presentationsWe describe three cases of HSC without documented candidemia and the challenges in establishing the diagnosis and adequately treating this condition. The first patient had a history of SCT for treatment of breast cancer and was scheduled for hemihepatectomy for suspected liver metastasis. A second opinion at our institute resulted in the diagnosis of hepatic candidiasis without prior documented candidemia, for which she was treated successfully with fluconazole. The second case demonstrates the limitations of (blood and tissue) cultures and the value of molecular methods to confirm the diagnosis. Case 3 illustrates treatment challenges, with ongoing dissemination and insufficient source control despite months of antifungal therapy, eventually resulting in a splenectomy.Literature reviewA structured literature search was performed for articles describing any patient with HSC and documented blood culture results. Thirty articles were available for extraction of data on candidemia and HSC. Seventy percent (131/187) of patients with HSC did not have documented candidemia. The majority of HSC events were described in hematologic patients, although some cases were described in patients with solid tumors treated with SCT (n = 1) or chemotherapy and a history of leukopenia (n = 2). Current guidelines and practices for diagnosis and treatment are described.ConclusionClinicians should be aware that HSC most often occurs without documented candidemia. In case of persistent or unexplained fever or lesions in the liver and/or spleen, a history of neutropenia should place disseminated candidiasis in the differential diagnosis. HSC is not limited to hematological patients and may occur in patients with solid tumors treated with bone marrow-suppressing chemotherapy or SCT. In the latter group, HSC as alternative diagnosis for hepatic metastasis should be considered when lesions are not typical for metastasis. This might prevent unnecessary surgery or inappropriate treatment.Implications for practiceTimely diagnosis of hepatosplenic candidiasis (HSC) is challenging, but can prevent further complications and dissemination, and may even prevent unnecessary invasive procedures. Clinicians should realize that HSC often occurs without documented candidemia and that sensitivity of blood cultures for candidemia is limited. HSC is not strictly limited to hematologic patients and might also occur in patients with solid tumors treated with intensive chemotherapy or stem cell transplantation. Increased awareness for HSC in patients with any history of neutropenia is of importance to increase detection and prevent serious sequelae.

Project description:ObjectivesTo evaluate how often the precise research question being addressed about an intervention (the estimand) is stated or can be determined from reported methods, and to identify what types of questions are being investigated in phase 2-4 randomised trials.DesignSystematic review of the clarity of research questions being investigated in randomised trials in 2020 in six leading general medical journals.Data sourcePubMed search in February 2021.Eligibility criteria for selecting studiesPhase 2-4 randomised trials, with no restrictions on medical conditions or interventions. Cluster randomised, crossover, non-inferiority, and equivalence trials were excluded.Main outcome measuresNumber of trials that stated the precise primary question being addressed about an intervention (ie, the primary estimand), or for which the primary estimand could be determined unambiguously from the reported methods using statistical knowledge. Strategies used to handle post-randomisation events that affect the interpretation or existence of patient outcomes, such as intervention discontinuations or uses of additional drug treatments (known as intercurrent events), and the corresponding types of questions being investigated.Results255 eligible randomised trials were identified. No trials clearly stated all the attributes of the estimand. In 117 (46%) of 255 trials, the primary estimand could be determined from the reported methods. Intercurrent events were reported in 242 (95%) of 255 trials; but the handling of these could only be determined in 125 (49%) of 255 trials. Most trials that provided this information considered the occurrence of intercurrent events as irrelevant in the calculation of the treatment effect and assessed the effect of the intervention regardless (96/125, 77%)-that is, they used a treatment policy strategy. Four (4%) of 99 trials with treatment non-adherence owing to adverse events estimated the treatment effect in a hypothetical setting (ie, the effect as if participants continued treatment despite adverse events), and 19 (79%) of 24 trials where some patients died estimated the treatment effect in a hypothetical setting (ie, the effect as if participants did not die).ConclusionsThe precise research question being investigated in most trials is unclear, mainly because of a lack of clarity on the approach to handling intercurrent events. Clear reporting of estimands is necessary in trial reports so that all stakeholders, including clinicians, patients and policy makers, can make fully informed decisions about medical interventions.Systematic review registrationPROSPERO CRD42021238053.

Project description:ObjectivesTo compare attitudes of mental health (MH) professionals towards trials of methylenedioxymethamphetamine-assisted psychotherapy (MDMA-AP), with a neutrally labelled pharmacotherapy trial.DesignA randomised controlled vignette study design, with experimenters blinded to group condition.SettingParticipants were recruited online via professional societies.ParticipantsPsychiatrists, psychologists and MH researchers from across Australia.InterventionsParticipants were randomly allocated to read a vignette about a trial of either MDMA-AP or a neutrally labelled pharmacotherapy.OutcomesComparison of the difference in four attitudes towards MDMA-AP and control: How likely they were to (1) recommend participating, or (2) object to participating in the trial; (3) their predicted efficacy; and (4) concerns about the safety of the trial.ResultsThere were no overall differences between professional's attitudes towards MDMA-AP (n=51) and the control pharmacotherapy (n=43) trial vignettes. Psychiatrists were less likely to recommend participation in the MDMA-AP than the control trial (d=0.72, p=0.02), but did not differ in other attitudes. Psychologists and researchers did not differ in any attitudes. The correlation between professional experience and both: (1) concern about, and (2) strength of objection to, the trial, was higher for MDMA-AP, than control (d=0.60, p=0.01 and d=0.40, p=0.03, respectively).ConclusionsPsychiatrists, but not psychologists or researchers showed more hesitancy in recommending trials of MDMA-AP versus an unknown pharmacotherapy. Experienced MH professionals were more likely to have negative views about MDMA-AP trials than less experienced MH professionals. This may reflect the experience of prior unfulfilled pharmacotherapy innovation or exuberance associated with fewer years of practice. Research into, and implementation of, MDMA-AP may face barriers with certain MH professionals, which will need be addressed if MDMA-AP continues to show promise as an efficacious treatment.Trial registration numberThe study design was registered with the ANZCTR (ACTRN12620001068954).

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Evaluation of the contribution of randomised cancer clinical trials evaluating agents without documented single-agent activity.

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Evaluation of the contribution of randomised cancer clinical trials evaluating agents without documented single-agent activity.

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