Radiosensitising strategies in locally advanced head and neck cancer: a systematic review and network meta-analysis of randomised controlled trials (RADIANCE-NMA)
Abstract
Background: Radiosensitiser enhance radiotherapy efficacy in locally advanced head and neck squamous cell carcinoma (HNSCC). Although cisplatin-based chemoradiotherapy is the standard-of-care, over two dozen radiosensitising strategies have been evaluated in randomised trials with no network meta-analysis comparing all drug classes.
Methods: PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov were searched from inception to 26 June 2026 for Phase IIb–III randomised controlled trials evaluating concurrent radiosensitiser therapy in adults with locally advanced head and neck squamous cell carcinoma (nasopharyngeal carcinoma excluded). Studies lacking overall survival data and induction-only comparisons were excluded. The primary outcome was overall survival (OS). All treatment-effect estimates are reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Data were independently extracted by two reviewers. Risk of bias in individual trials was assessed with the Cochrane Risk of Bias (RoB 2) tool and confidence in the network estimates using the Confidence in Network Meta-Analysis (CINeMA) framework. Random-effects network meta-analysis was done with frequentist (netmeta) and Bayesian (gemtc) frameworks. Between-study heterogeneity was quantified using the I2 statistic and τ2; publication bias and small-study effects were assessed using comparison-adjusted funnel plots and Egger's regression test. This study is registered with the Open Science Framework (https://osf.io/cygsh).
Findings: A total of 44 trials (13,768 patients; 84% male) were included in the primary analysis, with 23 additional trials in sensitivity analyses (67 total; 19,527 patients). Risk of bias showed some concerns in 39 of 44 (89%) primary trials on the Cochrane RoB 2 tool. Four treatments showed significant overall survival (OS) benefit versus radiotherapy alone: cisplatin plus 5-fluorouracil (hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.18–0.66), nimotuzumab plus weekly cisplatin (0.48; 0.29–0.81), weekly cisplatin (0.57; 0.44–0.74), and three-weekly cisplatin (0.79; 0.65–0.95). In the network estimate, weekly cisplatin was favoured over three-weekly (HR 0.73; 0.58–0.93); the underlying randomised trials were designed as non-inferiority comparisons. Between-study heterogeneity was moderate (I2 = 48.9%; τ2 = 0.036; Cochran Q = 37.15, df = 19, p = 0.008), with no detected inconsistency (design-by-treatment global test p = 0.88). The comparison-adjusted funnel plot and Egger's regression test showed no evidence of small-study effects, but are interpreted as exploratory given fewer than ten trials per edge on most comparisons. Grade 3–4 toxicity was highest with weekly cisplatin (pooled 71.6% across contributing trials) and lowest with immunotherapy combinations. Meta-regression confirmed enrolment era as a significant effect modifier (β = 0.23 post-2005 versus pre-2005; p = 0.010), consistent with the transition from two-dimensional or conformal radiotherapy in earlier trials to intensity-modulated radiotherapy in modern trials.
Interpretation: Platinum-based multi-agent chemoradiotherapy and weekly cisplatin are the most effective radiosensitising strategies for locally advanced HNSCC. Weekly cisplatin appears at least non-inferior to the widely used three-weekly schedule and may be favoured in network-integrated estimates, though confidence intervals do not exclude clinical equivalence. Neither cetuximab-based regimens (with radiotherapy or added to chemoradiotherapy) nor immune-checkpoint inhibitors added to cisplatin-based chemoradiotherapy significantly improved survival beyond standard cisplatin chemoradiotherapy. These findings provide a unified evidence framework for treatment selection and trial design.
Funding: None.
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BibTeX
@article{sreeram2026radiosensitising,
title = {{Radiosensitising strategies in locally advanced head and neck cancer: a systematic review and network meta-analysis of randomised controlled trials (RADIANCE-NMA)}},
author = {Sreeram MP and Prajwal Dange and Karthik N. Rao and Kevin J. Harrington and Jan B. Vermorken and Arlene A. Forastiere and William M. Mendenhall and Alfio Ferlito and Abbas Agaimy and Anna Luíza D. Araújo and Ameya Asarkar and Munita Bal and Jonathan J. Beitler and Carol Bradford and Patrick J. Bradley and Martina Bradová and Eelco de Bree and Remco de Bree and James C.H. Chow and Francisco J. Civantos and Andrés Coca Pelaz and Oded Cohen and Fernando Luiz Dias and Avraham Eisbruch and Veronica Fernández-Alvarez and Gustavo G. Fernandez Ranvier and Renata Ferrarotto and Ewa Florek and Alessandro Franchi and Nina Gale and Oreste Gallo and Eric M. Genden and Paweł Golusinski and Pim de Graaf and Orlando Guntinas-Lichius and Nathan W. Hales and Gyorgy B. Halmos and Marc Hamoir and Ehab Y. Hanna and Dana M. Hartl and Henrik Hellquist and Kevin Higgins and Justin M. Hintze and Akihiro Homma and David Kalfert and Jens Peter Klußmann and Luiz P. Kowalski and Suren Krishnan and Anne W.M. Lee and Reydson A. de Lima Souza and Fernando López and Manish Mair and Fernanda V. Mariano and Jean-Paul Marie and Lauge Hjorth Mikkelsen and Sarina Müller-Hübner and Alfons Nadal and Toshitaka Nagao and Cherie-Ann Nathan and Iain J. Nixon},
journal = {eClinicalMedicine},
year = {2026},
month = oct,
doi = {10.1016/j.eclinm.2026.104263},
url = {https://linkinghub.elsevier.com/retrieve/pii/S258953702600516X},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Radiosensitising strategies in locally advanced head and neck cancer: a systematic review and network meta-analysis of randomised controlled trials (RADIANCE-NMA)
AU - Sreeram MP
AU - Prajwal Dange
AU - Karthik N. Rao
AU - Kevin J. Harrington
AU - Jan B. Vermorken
AU - Arlene A. Forastiere
AU - William M. Mendenhall
AU - Alfio Ferlito
AU - Abbas Agaimy
AU - Anna Luíza D. Araújo
AU - Ameya Asarkar
AU - Munita Bal
AU - Jonathan J. Beitler
AU - Carol Bradford
AU - Patrick J. Bradley
AU - Martina Bradová
AU - Eelco de Bree
AU - Remco de Bree
AU - James C.H. Chow
AU - Francisco J. Civantos
AU - Andrés Coca Pelaz
AU - Oded Cohen
AU - Fernando Luiz Dias
AU - Avraham Eisbruch
AU - Veronica Fernández-Alvarez
AU - Gustavo G. Fernandez Ranvier
AU - Renata Ferrarotto
AU - Ewa Florek
AU - Alessandro Franchi
AU - Nina Gale
AU - Oreste Gallo
AU - Eric M. Genden
AU - Paweł Golusinski
AU - Pim de Graaf
AU - Orlando Guntinas-Lichius
AU - Nathan W. Hales
AU - Gyorgy B. Halmos
AU - Marc Hamoir
AU - Ehab Y. Hanna
AU - Dana M. Hartl
AU - Henrik Hellquist
AU - Kevin Higgins
AU - Justin M. Hintze
AU - Akihiro Homma
AU - David Kalfert
AU - Jens Peter Klußmann
AU - Luiz P. Kowalski
AU - Suren Krishnan
AU - Anne W.M. Lee
AU - Reydson A. de Lima Souza
AU - Fernando López
AU - Manish Mair
AU - Fernanda V. Mariano
AU - Jean-Paul Marie
AU - Lauge Hjorth Mikkelsen
AU - Sarina Müller-Hübner
AU - Alfons Nadal
AU - Toshitaka Nagao
AU - Cherie-Ann Nathan
AU - Iain J. Nixon
PY - 2026
DA - 2026/10/26
JO - eClinicalMedicine
DO - 10.1016/j.eclinm.2026.104263
UR - https://linkinghub.elsevier.com/retrieve/pii/S258953702600516X
AB - Background: Radiosensitiser enhance radiotherapy efficacy in locally advanced head and neck squamous cell carcinoma (HNSCC). Although cisplatin-based chemoradiotherapy is the standard-of-care, over two dozen radiosensitising strategies have been evaluated in randomised trials with no network meta-analysis comparing all drug classes. Methods: PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov were searched from inception to 26 June 2026 for Phase IIb–III randomised controlled trials evaluating concurrent radiosensitiser therapy in adults with locally advanced head and neck squamous cell carcinoma (nasopharyngeal carcinoma excluded). Studies lacking overall survival data and induction-only comparisons were excluded. The primary outcome was overall survival (OS). All treatment-effect estimates are reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Data were independently extracted by two reviewers. Risk of bias in individual trials was assessed with the Cochrane Risk of Bias (RoB 2) tool and confidence in the network estimates using the Confidence in Network Meta-Analysis (CINeMA) framework. Random-effects network meta-analysis was done with frequentist (netmeta) and Bayesian (gemtc) frameworks. Between-study heterogeneity was quantified using the I2 statistic and τ2; publication bias and small-study effects were assessed using comparison-adjusted funnel plots and Egger's regression test. This study is registered with the Open Science Framework (https://osf.io/cygsh). Findings: A total of 44 trials (13,768 patients; 84% male) were included in the primary analysis, with 23 additional trials in sensitivity analyses (67 total; 19,527 patients). Risk of bias showed some concerns in 39 of 44 (89%) primary trials on the Cochrane RoB 2 tool. Four treatments showed significant overall survival (OS) benefit versus radiotherapy alone: cisplatin plus 5-fluorouracil (hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.18–0.66), nimotuzumab plus weekly cisplatin (0.48; 0.29–0.81), weekly cisplatin (0.57; 0.44–0.74), and three-weekly cisplatin (0.79; 0.65–0.95). In the network estimate, weekly cisplatin was favoured over three-weekly (HR 0.73; 0.58–0.93); the underlying randomised trials were designed as non-inferiority comparisons. Between-study heterogeneity was moderate (I2 = 48.9%; τ2 = 0.036; Cochran Q = 37.15, df = 19, p = 0.008), with no detected inconsistency (design-by-treatment global test p = 0.88). The comparison-adjusted funnel plot and Egger's regression test showed no evidence of small-study effects, but are interpreted as exploratory given fewer than ten trials per edge on most comparisons. Grade 3–4 toxicity was highest with weekly cisplatin (pooled 71.6% across contributing trials) and lowest with immunotherapy combinations. Meta-regression confirmed enrolment era as a significant effect modifier (β = 0.23 post-2005 versus pre-2005; p = 0.010), consistent with the transition from two-dimensional or conformal radiotherapy in earlier trials to intensity-modulated radiotherapy in modern trials. Interpretation: Platinum-based multi-agent chemoradiotherapy and weekly cisplatin are the most effective radiosensitising strategies for locally advanced HNSCC. Weekly cisplatin appears at least non-inferior to the widely used three-weekly schedule and may be favoured in network-integrated estimates, though confidence intervals do not exclude clinical equivalence. Neither cetuximab-based regimens (with radiotherapy or added to chemoradiotherapy) nor immune-checkpoint inhibitors added to cisplatin-based chemoradiotherapy significantly improved survival beyond standard cisplatin chemoradiotherapy. These findings provide a unified evidence framework for treatment selection and trial design. Funding: None.
SN - 2589-5370
ER -