Protons vs Photons is a timely comparison as photon (X-ray) radiotherapy remains the global standard because it is widely available, highly versatile, and supported by decades of mature outcomes data across disease sites. Proton therapy, by contrast, offers a distinct physical advantage—lower integral dose to normal tissues—which can be clinically meaningful when targets abut critical organs, when long-term toxicity is a dominant concern, or when prior irradiation limits the safe use of additional photon dose.
By the end of 2025, the discussion has moved beyond dosimetry toward comparative clinical evidence, including randomized trials and large real-world datasets. The field is increasingly focused on where normal-tissue sparing translates into tangible patient benefit—not only improved quality of life and reduced acute/late toxicity, but also the ability to deliver effective tumor dose more safely in complex scenarios such as reirradiation. Pediatrics remains a cornerstone indication for protons, where minimizing dose to developing organs is central to reducing late effects, secondary malignancy risk, and neurocognitive or endocrine sequelae.
Importantly, this is not a “quality-of-life only” conversation. A key question at the end of 2025 is where proton therapy can preserve or improve disease control by enabling better target coverage, safer dose escalation, or more definitive treatment in anatomically constrained cases—while recognizing that for many routine indications, modern photon techniques continue to provide excellent tumor control with strong evidence and broad accessibility.
Head And Neck Cancer
Frank et al., published in The Lancet in 2025, reported results of a randomised, multicentre, open-label, phase 3 non-inferiority trial comparing intensity-modulated proton therapy (IMPT) versus intensity-modulated photon radiotherapy (IMRT), both delivered to 70 Gy in 33 fractions with concurrent systemic therapy, in patients with stage III–IV oropharyngeal cancer treated across 21 US centres. With a median follow-up of 3.2 years, IMPT met the prespecified non-inferiority criterion for progression-free survival (3-year PFS 82.5% with IMPT vs 83.0% with IMRT; HR 0.88), while also showing an overall survival advantage at 5 years (90.9% vs 81.0%; HR 0.58).
Disease control outcomes were comparable between arms, with similar rates of local, regional, and distant failure. High-grade toxicities were consistently lower with IMPT, including severe lymphopenia, dysphagia, xerostomia, and gastrostomy-tube dependence. Treatment-related and post-progression deaths occurred more frequently in the IMRT group, and the authors concluded that IMPT is an evidence-based standard-of-care option for appropriately selected patients with oropharyngeal cancer.
Dasiukevich et al., published in 2025 in Medical Physics: The International Journal of Medical Physics Research and Practice, used a computational modelling approach to compare secondary cancer risk after head-and-neck radiotherapy with photons versus protons. In 20 patients, the authors generated paired clinical treatment plans (one photon, one proton), estimated dose both within and beyond the planning CT by stitching an adjustable whole-body digital phantom to each patient dataset, and calculated lifetime secondary cancer risk across relevant organs.
For protons, they additionally modelled LET and evaluated six variable RBE models alongside the conventional constant RBE of 1.1. Overall, photon therapy was estimated to confer a higher secondary cancer risk than proton therapy—about 1.8-fold on average when compared with protons using RBE 1.1—with the risk ratio remaining in a similar range (approximately 1.6–2.0) across the variable RBE models. The study supports the expectation that proton dose sparing translates into lower estimated secondary malignancy risk in head-and-neck cancer, while highlighting the influence of RBE assumptions on risk estimates.
Chang et al., published in 2024 in Radiotherapy and Oncology, reported a national retrospective cohort study from Taiwan comparing oncologic outcomes of proton therapy versus IMRT for head and neck squamous cell carcinoma treated with curative-intent radiotherapy (2015–2019).
Using Taiwan Cancer Registry data across three proton-capable institutes and 17 IMRT institutes, the authors applied 3:1 propensity score matching to reduce confounding and evaluated outcomes with Cox models. In the matched cohort (n=982), proton therapy was associated with significantly lower risks of all-cause mortality (aHR 0.43), cancer-specific death (aHR 0.44), and locoregional recurrence (aHR 0.61) compared with IMRT, suggesting improved survival and disease control with proton therapy in this real-world dataset.
Results from a randomized phase II trial in nasopharyngeal carcinoma (NPC) compared IMRT plus a carbon-ion radiotherapy boost (CIRT) versus IMPT plus CIRT. A total of 136 patients were enrolled (68 per arm) with a median follow-up of 51.5 months. The primary endpoint was the rate of grade ≥2 xerostomia at 6 months after radiotherapy: 29% with IMRT+CIRT versus 16% with IMPT+CIRT (p=0.088).
Three-year overall survival was 100% versus 98.5% (p=0.99), and three-year progression-free survival was 90.8% versus 88.1% (p=0.64), indicating comparable disease control between arms. Overall, adding protons (IMPT) to CIRT reduced the risk of clinically significant xerostomia at 6 months while maintaining similar survival outcomes. These findings (NCT04528394) were presented at ASTRO 2025.
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Breast Cancer
RADCOMP is the largest phase III randomized trial to directly compare proton (PrRT) versus photon (PhRT) radiation in women with nonmetastatic breast cancer receiving regional nodal irradiation, including internal mammary nodes. In 1,239 patients (624 protons, 615 photons; median age 50), patient-reported outcomes were collected before RT, at completion, and at 1 and 6 months using PROMIS Fatigue, BREAST-Q, FACT-B, PRO-CTCAE (eg, shortness of breath, chest pain), and FACIT. At 6 months, fatigue, cosmetic outcomes, and overall quality of life were similar between groups.
A signal for less dyspnea with protons seen on unadjusted analysis was no longer significant after correction for multiple comparisons, while several FACIT items reflecting a more positive treatment experience (eg, willingness to recommend treatment or choose it again) favored protons and remained significant after stricter statistical adjustment. Longer-term results on locoregional control and cardiovascular events are expected in future reports. These findings were presented at ASTRO 2025 by Shannon MacDonald.
Singh et al., published in 2025 in JNCI Cancer Spectrum, retrospectively evaluated cardiovascular risk profiles and outcomes in 599 breast cancer patients treated with proton therapy at the Maryland Proton Treatment Center (June 2016–December 2021). With a median follow-up of 26 months, Black patients comprised 31.6% of the cohort and had significantly higher baseline rates of hypertension and cardiopulmonary comorbidities, as well as higher median BMI, compared with non-Black patients—differences that persisted at follow-up. Black women also more frequently had triple-negative disease and were more likely to receive neoadjuvant chemotherapy.
After proton therapy, pulmonary events occurred more often in Black patients, with a 2.6-fold higher odds versus the non-Black cohort (OR 2.60, 95% CI 1.39–4.88). The authors conclude that Black women presenting for proton therapy carry a higher baseline cardiopulmonary risk burden alongside more aggressive disease features, underscoring the rationale for organ-sparing radiation approaches—particularly for historically marginalized populations.
CNS tumors
Lesueur et al., published in 2024 in BMC Cancer, described COG-PROTON-01, the first randomized phase III prospective trial designed to compare long-term toxicity of fractionated proton therapy (PRT) versus photon radiotherapy (XRT) for low-grade cavernous sinus (skull base) meningioma. The study’s primary objective is to determine whether protons reduce long-term neurocognitive and functional deterioration at 5 years after treatment, using a composite endpoint that includes standardized neurocognitive testing across five domains (attention, executive function, verbal memory, working memory, and processing speed) alongside visual, hearing, neurological, and endocrinological assessments.
A total of 160 patients will be randomized 1:1 (80 per arm) with stratification by age, sex, and baseline MoCA score; enrollment began in 2023 (NCT05895344). The rationale is that, given the excellent prognosis and long life expectancy in this population, minimizing late effects is critical—while the dosimetric advantages of protons are well established, the magnitude of clinical benefit versus modern photon techniques remains uncertain and requires randomized evidence.
At ASTRO 2025, investigators reported results from a randomized study asking whether dose escalation with protons could improve overall survival in newly diagnosed glioblastoma without increasing toxicity. Eligible patients had KPS ≥70 and a small residual volume (≤5 cm), underwent central pathology confirmation with MGMT assessment, and received standard chemoradiation with temozolomide. Patients were randomized to standard photon RT to 60 Gy versus proton dose escalation to 75 Gy in 30 fractions using a simultaneous integrated boost.
Across 193 patients treated between 2014 and 2022, there were no statistically significant differences in toxicity between arms. Grade ≥3 lymphopenia occurred in 23.4% with 60 Gy photons versus 17.1% with 75 Gy protons, and grade ≥4 neurologic toxicity was 1.8% versus 5%, respectively. Median overall survival was 22.8 months with 75 Gy protons compared with 22.0 months with 60 Gy photons (HR 0.81; 70% CI 0.67–0.98; p=0.11), with absolute OS improvements of 6.8% at 2 years and 4.6% at 3 years; the effect persisted after adjustment for MGMT status and RPA class. The presenters concluded that proton dose escalation met the prespecified hypothesis of improved survival without increased lymphopenia and provides the rationale for a confirmatory phase III trial.
Written by Aren Karapetyan, MD