Lower Radiation Dose Tied to Less Trouble Swallowing in HPV Throat Cancer

Patients with human papillomavirus (HPV)-associated oropharyngeal cancer, a cancer in the middle part of the throat, may have fewer swallowing and voice problems with a lower dose of radiation. Six months after treatment, patients who responded well to chemotherapy and received less radiation reported fewer symptoms than those who received the standard dose.

The results come from an analysis of two phase 2 trials run by the ECOG-ACRIN Cancer Research Group, published in JCO Oncology Advances.

The earlier trial, E2399, found that patients with HPV-associated oropharyngeal cancer had higher response rates and longer survival than patients whose cancer was not linked to HPV. Those results fueled interest in treatment that keeps cure rates high with fewer short- and long-term side effects. The follow-up trial, E1308, tested whether patients whose tumors disappeared on exam after chemotherapy could receive 54 gray (Gy), the unit used to measure radiation dose, instead of the standard 69.3 Gy. The researchers noted that the 23% reduction could ease long-term swallowing problems, taste changes, mucus production and dry mouth.

What did the E1308 trial find about swallowing and voice after lower-dose radiation?

Six months after treatment, patients who received 54 Gy reported less difficulty swallowing solid food on the Vanderbilt Head and Neck Symptom Survey Version 2 (VHNSSv2), a 50-item questionnaire in which patients rate head and neck cancer symptoms from 0 (none) to 10 (severe). Scores for swallowing solids rose by a median of 1.38 points from before treatment in the lower-dose group, compared with 3.31 points in the standard-dose group. Voice problems did not increase with the lower dose (0.0) but rose by 1.0 point with the standard dose.

The lower-dose group also reported less trouble swallowing liquids, less dry mouth and fewer limits in moving the neck and shoulders. Scores for the lower-dose and standard-dose groups were 0.0 and 0.5, respectively, for swallowing liquids; 3.5 and 5.1 for dry mouth; and 0.0 and 1 for neck and shoulder movement. These differences were large enough that chance was an unlikely explanation.

A second questionnaire, the Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN), showed a smaller drop in voice strength and quality with the lower dose. The same survey showed less difficulty eating solid food in the lower-dose group, although that gap fell short of the level researchers use to rule out chance.

Scores for mouth pain, nutrition, excess mucus, taste and smell changes and teeth problems were also lower with 54 Gy. The researchers described those differences as clinically important, but the gaps could have come about by chance, likely because few patients received the standard dose.

“The cardinal finding of this analysis is that swallowing dysfunction and oral symptoms are very prevalent early after [chemotherapy and radiation] but less evident at later time points,” wrote the researchers.

At 12 months, 40% of patients who received the lower dose rated their difficulty swallowing solids at 2 or higher on the survey's 0-to-10 scale, compared with 89% of patients who received the standard dose. Nutrition problems at that level affected 10% and 44% of patients, respectively. Fewer patients completed the surveys at later time points, so the researchers focused their results on the six-month mark. Broader quality-of-life surveys, which measured fatigue, physical activity and the ability to handle daily tasks such as bathing, dressing, shopping and cooking, did not detect differences between the dose groups at any time point. According to the researchers, the surveys designed for head and neck cancer were better at capturing changes in side effects.

How did lower-dose radiation on E1308 compare with the radiation used on E2399?

E2399 treated 69 patients with oropharyngeal cancer, including cancers linked and not linked to HPV. Patients received paclitaxel and carboplatin before radiation, followed by 70 Gy of three-dimensional conformal radiation therapy (3DRT) over seven weeks with weekly paclitaxel. E1308 used intensity-modulated radiation therapy (IMRT), a highly targeted form of radiation, and patients in the lower-dose group received 54 Gy over 5.5 weeks.

In an exploratory comparison of patients whose cancer had not progressed 12 months after treatment, patients on E1308 reported no decline from before treatment in their ability to eat solid food or to eat the foods they liked on the FACT-HN. Patients on E2399 reported a decline on both measures.

Who was in the E1308 trial of lower-dose radiation for HPV-associated oropharyngeal cancer?

E1308 included 80 eligible patients with stage 3 to 4b HPV-associated oropharyngeal cancer that could be removed with surgery. The median age was 57, and 84% were not current smokers.

Patients first received three cycles of induction chemotherapy, or chemotherapy given before radiation, with paclitaxel and cisplatin plus Erbitux (cetuximab). The trial assigned 54 Gy of IMRT with weekly Erbitux to patients whose main tumor disappeared on physical exam after chemotherapy, called a complete clinical response, and the standard 69.3 Gy of IMRT with weekly Erbitux to patients without a complete response. A total of 62 patients (78%) received the lower dose.

Among patients who received the lower dose, the two-year progression-free survival rate, meaning the share of patients alive without their cancer growing or spreading, was 81%. Among patients who did not have a complete response and received 69.3 Gy, the two-year progression-free survival rate was 65%.

Patients completed symptom surveys before treatment and at six, 12, 24 and 30 months after treatment. The survey analysis included 51 patients whose cancer had not progressed at 12 months, nine of whom received the standard dose and 42 the lower dose.

What side effects did patients have with lower-dose radiation on the E1308 trial?

Patients who received 69.3 Gy with Erbitux had more frequent grade 3 or higher mouth sores, known as mucositis, than patients who received 54 Gy (47% versus 30%). The standard-dose group also had more difficulty swallowing (29% versus 15%), acne-like rash (24% versus 12%), skin irritation from radiation (12% versus 7%), blood clots (6% versus 0%) and low levels of lymphocytes, a type of white blood cell (35% versus 12%). Grade 4 side effects occurred in fewer than 5% of patients in each dose group.

Compared with patients who received 54 Gy on E1308, patients who received 3DRT on E2399 had more grade 3 or higher mouth sores (58% versus 29%), difficulty swallowing (39% versus 15%), inflammation of the esophagus (8% versus 0%) and infections (8% versus 0%). Patients who received the lower dose on E1308 had more grade 3 or higher low lymphocyte counts (13% versus 3%), which the researchers attributed to the more intensive three-drug chemotherapy given before radiation.

What are the limitations of the E1308 radiation dose study?

Only nine patients received the standard dose, which limited some comparisons between groups. Fewer patients completed the surveys at later time points, possibly because of the time the questionnaires took, and some patients left the analysis by 12 months because their cancer came back or because of other events.

Patients were not assigned to their dose groups at random. The comparison with E2399 also included patients whose cancer was not linked to HPV, which the researchers noted introduces variation and potential bias. The two radiation techniques also differ in tumor margins, dose to the salivary glands and throat muscles used for swallowing, and risk of lymphedema, or swelling.

“Ultimately, adequately powered randomized trials using appropriate [patient-reported outcome] instruments will be needed to determine the optimal approaches for HPV-related disease,” the researchers concluded.

References

1. Cmelak AJ, et al. “Patient-Reported Toxicity With Radiation Deintensification in Human Papillomavirus–Associated Oropharynx Cancer: ECOG-ACRIN E2399 and E1308.” JCO Oncology Advances. Published September 29, 2026.

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