IMPT and IMRT Yield Similar QOL and Disease Control in Oropharyngeal Cancer

Intensity-modulated proton therapy (IMPT) was associated with similar late physical quality-of-life (QOL) scores, local disease control, gastronomy tube dependence, and overall survival (OS) rates compared with intensity-modulated radiation therapy (IMRT) among patients with locally advanced oropharyngeal squamous cell carcinoma, according to findings from the phase 3 TORPEdO trial (ISRCTN16424014) published in the Lancet.¹

At 12 months, the mean University of Washington QOL (UW-QOL) physical composite score was 78.3 in the IMPT group (n = 136) vs 77.1 in the IMRT group (n = 69; difference, 1.3; 97.5% CI, –3.7 to 6.2; P = .56). Furthermore, gastrostomy tube dependence or severe weight loss occurred in 18% of patients in the IMPT group compared with 6% of patients in the IMRT group (adjusted OR, 2.80; 97.5% CI, 0.75-10.41; P = .079), a result largely driven by a higher incidence of grade 3 weight loss in the IMPT arm.

“Both modalities are effective, and in health care settings where IMPT is not used routinely for oropharyngeal squamous cell carcinoma, IMRT remains the standard of care [SOC],” lead study author David J. Thomson, MD, and coauthors wrote in the paper.

Thomson is affiliated with The Christie NHS Foundation Trust and the Division of Cancer Sciences in the School of Medical Sciences at the University of Manchester, as well as the Department of Molecular and Clinical Cancer Medicine at the University of Liverpool in England.

What was the rationale for comparing IMPT with IMRT in oropharyngeal cancer?

IMRT with concurrent chemotherapy is the current SOC for patients with locally advanced oropharyngeal squamous cell carcinoma. However, severe late adverse effects (AEs) can affect QOL. Notably, poor swallowing outcomes have been shown to affect some patients 2 years after treatment, and many patients experience a persistent decline in UW-QOL physical functioning score at 12 months after treatment.

Furthermore, a multi-institutional pooled analysis showed that among 1238 patients with stage III or IV oropharyngeal squamous cell carcinoma who received IMRT and concurrent chemotherapy, 8.6% were dependent on a gastronomy tube at 1 year and 4.4% at 2 years.² This rate was 5% among patients with stage I or II disease, 5.2% for those with stage III or IV and T1-T2/N0-N2 disease, and 10.1% for those with stage III or IV and T3-T4 or N3 disease.

IMPT has been shown to reduce doses of radiation to organs at risk, including swallowing structures, the contralateral parotid gland, and the oral cavity, which may lead to fewer adverse physical effects vs IMRT.¹ For instance, a matched cohort study demonstrated that IMPT (n = 50) was associated with reduced 12-month rates of gastronomy tube dependence or severe weight loss compared with IMRT (n = 100; OR, 0.23; 95% CI, 0.07-0.73; P = .01).³

What was the design of the TORPEdO trial?

This multicenter, randomized trial conducted at 20 UK National Health Service hospitals enrolled 205 patients with newly diagnosed, locally advanced oropharyngeal cancer suitable for concurrent chemoradiotherapy.¹ Patients were randomly assigned 2:1 to receive:

• IMPT at 70 Gy in 33 fractions plus high-dose cisplatin, or
• IMRT at the same dose and fraction schedule with cisplatin

The trial used co–primary end points assessed at 12 months: the UW-QOL physical composite score and the combined rate of gastrostomy tube dependence or severe weight loss (≥ 20% from baseline). Secondary end points included OS, locoregional control, and safety.

What were the baseline characteristics of the TORPEdO study population?

Between February 2020 and June 2023, 205 patients were assigned to treatment. Most were male (80%) and White British (94%), with a median age of 57.1 years (range, 52.7-62.3). Baseline disease features included T3 or T4 disease (48%) and bilateral neck lymph node involvement (22%). Most patients (96%) had p16-positive disease.

What were the patient-reported outcome and survival findings from the trial?

Although UW-QOL physical composite scores declined during radiotherapy, they increased steadily up to 12 months post treatment in both groups. By week 6 post chemoradiotherapy, any initial differences between the groups had resolved. At 12 months, approximately one-fifth of patients in both arms reported being able to taste only some foods, and two-fifths reported having too little saliva. Other patient-reported measures, including the MD Anderson Dysphagia Inventory and EORTC core QOL questionnaire global health scores, also showed no significant differences between treatment modalities at 12 months.

In terms of disease control, the 24-month OS rate was 95% in both the IMPT and IMRT arms (HR, 1.6; 95% CI, 0.3-8.8; P = .47). The 24-month freedom from locoregional recurrence was 94% (99% CI, 86%-98%) with IMPT vs 97% (99% CI, 82%-100%) with IMRT (HR, 2.6; 95% CI, 0.5-12.4; P = .24).

What safety signals were observed with IMPT vs IMRT in TORPEdO?

IMPT was associated with a lower incidence of grade 3 acute radiotherapy-related AEs (50%) than IMRT (72%; P = .0035). Grade 3 oral pharyngeal mucositis occurred in 37% of patients in the IMPT group vs 54% of those in the IMRT group, and grade 3 dysphagia was reported in 12% and 24% of patients, respectively.

However, grade 3 late AEs were numerically more frequent with IMPT (25%) than with IMRT (14%; P = .081). This difference was primarily attributed to weight loss observed from month 3 onward and to hearing impairment. Serious AEs occurred in 12 patients, with acute kidney injury and thromboembolism being the most common. There were no treatment-related deaths.

What were the primary limitations of the TORPEdO trial?

The investigators identified several limitations that may affect the generalizability and interpretation of the results:

• Lack of ethnic diversity: Most patients self-reported as White, meaning minority ethnic groups were underrepresented relative to the broader population treated for oropharyngeal cancer.
• Modified intention-to-treat analysis: The primary analysis focused on a modified population that excluded patients with early recurrence or death, potentially introducing bias.
• Lower IMRT event rate: The observed event rate for the clinical primary end point in the IMRT group was lower than the 25% assumed for the sample size calculation, potentially affecting the study’s power to detect certain differences. However, the authors noted that since event rates did not favor the IMRT group, the overall conclusions of the study would not have been affected by using a larger sample size.
• Planning and biological uncertainties: Variations in proton planning techniques, robustness parameters, and the use of a fixed relative biological effectiveness of 1.1 may limit the reproducibility of the trial’s findings across proton centers at different institutions.

“The trial provides robust data on [AE] profiles and trajectories with modern treatments,” the authors concluded. “Contemporary radiation contouring and advanced IMRT planning improved outcomes compared with previous series.”

References

1. Thomson DJ, Price JM, Tyler M, et al. Proton beam therapy for oropharyngeal cancer (TORPEdO): a phase 3, randomised controlled trial. Lancet. 2026;407(10535):1259-1275. doi:10.1016/S0140-6736(26)00314-4
2. Setton J, Lee NY, Riaz N, et al. A multi-institution pooled analysis of gastrostomy tube dependence in patients with oropharyngeal cancer treated with definitive intensity-modulated radiotherapy. Cancer. 2015;121(2):294-301. doi:10.1002/cncr.29022
3. Blanchard P, Garden AS, Gunn GB, et al. Intensity-modulated proton beam therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for patients with oropharynx cancer – a case matched analysis. Radiother Oncol. 2016;120(1):48-55. doi:10.1016/j.radonc.2016.05.022