What is the risk-benefit balance for pediatric cancer phase 1 trials measuring benefit by response rate and risk by Grade 3, 4, or 5 drug related events?
PubMed and EMBASE were searched systematically from 2004 to 2015. PubMed search performed: 1 Mar 2015. EMBASE search performed: 28 Feb 2015.
Full details of the search strategies can be found in the accompanying PDF document (see link below).
Types of study to be included
Pedatric cancer phase 1, defined as "Small sample size, non-randomized, dose escalation studies that define the recommended dose for subsequent study of a new drug in each schedule tested." We also include phase 1 and 2 altogether with results in phase 1 reported separately.
Condition or domain being studied
Pediatric cancer phase 1 trials. Pediatric cancer phase 1/2 with separate results in phase 1. We include all types of cancer - both solid tumours and hematological malignancies of any type and stage.
We will include studies where all or most participants are under 21 years old and the study is indicated as pediatric. We will exclude studies where most participants are 18 years old and/or older.
We will include studies with patients with (1) solid tumors, (2) haematological malignancies or 1&2 altogether.
We will exclude patients with benign tumor or other disease only, without cancer. We will also exclude studies with healthy volunteers.
We will include phase 1 and phase 1/2 (if phase 1 results reported separately) studies where chemotherapy or targeted therapy was the only treatment, drugs were administered systemically:
1. Chemotherapy – cytotoxic drugs schedules monotherapy or polytherapy.
2. Targeted therapy (monoclonal antibodies or small molecule or antibody drug conjugates, in accordance with definitions provided in Karp & Falchook’s Handbook of Targeted Cancer Therapy, 2015) also combinations of targeted therapies.
3. 1&2 altogether. We will exclude studies on drugs administered topically or regionally only (i.e. directly to the tumour without any systemic effects or minimal systemic effects). We will also exclude studies reporting only pharmacokinetics and/or pharmacodynamics of a tested treatment.
We will also exclude studies where surgery, and radiotherapy were the only treatment or were used together with chemotherapy/targeted therapy. We will exclude supportive care without anticancer agents and other types of drugs and treatments i.e. antiviral agents or non-specific immunotherapy (eg. Inteferon , interleukins, cytokines, immunostimmulator, sagramostim, filgastrim, granulocyte-macrophage colony-stimulating factor [GM-CSF]), cancer vacccine, oncolytic virus therapy.
Quantify the average risk/benefit balance for phase 1 cancer studies, measuring benefit by response rate and risk by Grade 3,4, or 5 drug related events.
A complete or partial response rate will be measured as defined by the study authors. Grade 3,4, or 5 drug related events will be measured as defind by Common Terminology Criteria for Adverse Events v3.0.
Dosing strategies, citation of preclinical evidence, recommendation of further studies, the number of patients receiving recommended dose, the top level administred dose.
Data extraction, (selection and coding)
Data extraction form was piloted. We will extract details on general study design, population, intervention, outcomes and preclinical evidence.
Data will be extracted independently by two reviewers. Any disagreements will be resolved by discussion, and, when necessary, a third person - an arbiter - will be involved.
Risk of bias (quality) assessment
Strategy for data synthesis
If possible the estimates will be pooled using the inverse variance method. Heterogeneity will be assessed using Q test and I-squared. If pooling is not possible the data will be presented narratively.
Analysis of subgroups or subsets
We will explore heterogeneity between the studies according to several characteristics, such as the type of treatment, type of disease (solid tumor, hematological malignancy), funding, etc.
W will subit this systematic review to a peer-review journal. We also pla to disseminate the results through the workshops and conferences. E.g. a poster at the 23rd Cochrane Colloquium and a presentation at the 29th European Conference for Philosophy of Medicine and Healthcare and others.
Dr Marcin Waligora, REMEDY, Research Ethics in Medicine Study Group, Department of Philosophy and Bioethics, Jagiellonian University, Medical College, Poland Dr Malgorzata Bala, Clinical Decision Making Unit, 2nd Department of Internal Medicine, Jagiellonian University Medical College, Poland Mrs Magdalena Koperny, Department of Public Health and Health Promotion, Regional Sanitary-Epidemiological Station in Krakow, Poland Dr Rafal R. Jaeschke, Department of Affective Disorders, Chair of Psychiatry, Jagiellonian University Medical College, Poland Mrs Agnieszka Kargul, The Agency for Health Technology Assessment and Tariff System, Poland Dr Jan Piasecki, REMEDY, Research Ethics in Medicine Study Group,Department of Philosophy and Bioethics, Jagiellonian University, Medical College, Poland Dr Dominika Nowis, Genomic Medicine, the Medical University of Warsaw, Poland; Laboratory of Experimental Medicine, Centre of New Technologies, University of Warsaw, Poland Professor Jonathan Kimmelman, Studies of Translation, Ethics and Medicine (STREAM),Studies Biomedical Ethics Unit / Experimental Medicine / Social Studies of Medicine McGill University, Montréal, QC, Canada
Anticipated or actual start date
23 March 2015
Anticipated completion date
30 November 2015
National Science Centre, Poland, DEC-2011/03/D/HS1/01695
Formal screening of search results against eligibility criteria
Risk of bias (quality) assessment
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