ArticleBMC cancer2021
Is more better? An analysis of toxicity and response outcomes from dose-finding clinical trials in cancer.
Article in BMC cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
15 citing papers in PubMed, 2 syntheses or guidelines pooled it, 18 citations in OpenAlex.
- Model-based meta-analysis of individual patient data for the characterization of intravenous 5-fluorouracil population pharmacokinetics.Cancer chemotherapy and pharmacology · 2026Pooled it
- Evolving or immutable - phase I solid tumor trials in the era of precision oncology.Investigational new drugs · 2024Pooled it
- Implementing Project Optimus in Oncology Dosage Optimization: Where are We Now?Therapeutic innovation & regulatory science · 2026Article
- Generalized Pairwise Comparisons in Dose Optimization Oncology Trials: Beyond Safety to Multi-outcome Dose Selection.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- From Innate Immunity to Cancer Therapy: Antimicrobial Peptides as Emerging Anticancer Agents.International journal of molecular sciences · 2026Review
- PRO-ADD: Patient-empowered dose-finding trials integrating safety, preliminary efficacy and patient-reported outcomes for optimal dose selection.Statistical methods in medical research · 2026Article
- DOSET: dose optimization with simultaneous efficacy and toxicity evaluation, motivated by a first-in-human phase I CAR T lymphoma trial.ESMO open · 2026Article
- A marginal structural model for normal tissue complication probability.Biostatistics (Oxford, England) · 2025Article
- Review
- Toxicity Adaptive Lists Design: A Practical Design for Phase I Drug Combination Trials in Oncology.JCO precision oncology · 2024Article
- REDOMA: Bayesian random-effects dose-optimization meta-analysis using spike-and-slab priors.Statistics in medicine · 2024Article
- Evolving or Immutable - Phase I Solid Tumor Trials in the Era of Precision Oncology.Research square · 2024Article
- A generalized phase 1-2-3 design integrating dose optimization with confirmatory treatment comparison.Biometrics · 2024Article
- Implementing the time-to-event continual reassessment method in the presence of partial orders in a phase I head and neck cancer trial.BMC medical research methodology · 2024Article
- Antibody-Drug Conjugates: Ushering in a New Era of Cancer Therapy.Pharmaceutics · 2023Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundThe overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies.
methodsWe extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions.
resultsWe found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption.
conclusionsOur conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that may be harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.