Proton Therapy Shows Survival Benefit Over Photon Radiotherapy in Advanced Oropharyngeal Cancer: Phase 3 Trial
USA: A large US-based phase III clinical trial has shown that proton radiotherapy offers a meaningful survival advantage and reduced toxicity compared with conventional photon radiotherapy for patients with advanced oropharyngeal cancer.
The multicentre study, published in The Lancet, was led by Prof. Steven J. Frank from the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Centre, Houston, and provides high-level evidence supporting proton therapy as a new standard of care in this setting.
Radiotherapy remains a cornerstone of treatment for oropharyngeal cancer, particularly for stage III and IV disease. However, the current standard approach—intensity-modulated radiation therapy (IMRT), which uses high-energy X-rays, has been associated with substantial acute and long-term toxicities. These adverse effects have driven interest in alternative technologies that can maintain tumour control while limiting damage to surrounding healthy tissues. Intensity-modulated proton therapy (IMPT) has emerged as a promising option, as protons deliver radiation more precisely to the tumour with less exit dose.
The trial enrolled 440 adults with locally advanced oropharyngeal cancer across 21 cancer centres and universities in the United States between 2013 and 2022. Participants were randomly assigned to receive either IMPT or IMRT, both delivered concurrently with systemic therapy selected according to standard clinical guidelines. All patients received a total radiation dose of 70 Gy to the primary tumour and involved lymph nodes.
The following were the key findings of the study:
- IMPT achieved non-inferiority for progression-free survival after a median follow-up of just over three years.
- Three-year progression-free survival was 82.5% with proton therapy and 83.0% with photon therapy, with comparable outcomes maintained at five years.
- Overall survival was higher with IMPT, with 90.9% of patients alive at five years compared with 81.0% in the IMRT group.
- Proton therapy was associated with a significantly lower risk of death than photon radiotherapy.
- Rates of local recurrence, regional recurrence, and distant metastases were similar between the two treatment groups, indicating comparable disease control.
- Severe treatment-related toxicities occurred more frequently in patients treated with photon radiotherapy.
- High-grade lymphopenia, dysphagia, xerostomia, and gastrostomy tube dependence were more common in the IMRT group than in the IMPT group.
- Treatment-related deaths and deaths following disease progression were higher with photon therapy compared with proton therapy.
According to the investigators, these findings demonstrate that proton therapy not only preserves disease control but also improves survival while reducing the burden of treatment-related side effects. The authors noted that IMPT effectively de-intensifies chemoradiation compared with IMRT, offering both clinical and quality-of-life benefits.
Although longer follow-up and additional trials will further refine patient selection, this study provides robust evidence that IMPT represents a safer and more effective radiotherapy option for patients with advanced oropharyngeal cancer, particularly in an era of rising HPV-associated disease.
Reference:
Frank SJ, Busse PM, Lee JJ, Rosenthal DI, Hernandez M, Swanson DM, Garden AS, Gunn GB, Patel SH, Snider JW, Ma DJ, Molitoris JK, Lee NY, Parvathaneni U, McDonald MW, Kalman NS, Lin A, Mohammed N, Henson C, Hyde C, Bajaj GK, Katz SR, Dagan R, Morrison WH, Reddy JP, Fuller CD, Shah SJ, Phan J, Chronowski GM, Mayo L, Sturgis EM, Ferrarotto R, Zhu XR, Zhang X, Wang L, Hutcheson KA, El-Naggar AK, Moreno AC, Lee A, Spiotto MT, Gross ND, Lai SY, Liao JJ, Paly J, Liao Z, Foote RL; University of Texas MD Anderson Cancer Center Clinical Trial Consortium. Proton versus photon radiotherapy for patients with oropharyngeal cancer in the USA: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet. 2025 Dec 11:S0140-6736(25)01962-2. doi: 10.1016/S0140-6736(25)01962-2. Epub ahead of print. PMID: 41391462.
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