Disease control was not compromised and toxicities not increased when researchers used reduced radiation doses and volumes of concurrent chemoradiotherapy (CCRT) on elective nodal regions in patients with human papillomavirus (HPV)-positive oropharyngeal cancer treated with cisplatin or other chemotherapy regimens, according to a recent study in JAMA Oncology.

Two-year locoregional control, progression-free survival, and overall survival rates were high with this de-escalating regimen, despite roughly one-third of patients in the study having cT3-cT4 disease.

“Our institution has used a systematic approach of radiotherapy de-escalation since March 2017 for all patients with HPV-positive [oropharyngeal carcinoma] OPC undergoing CCRT, with further reduction of the elective radiation dose to 30 Gy, based on historical data on HPV-related cancers and modern HPV-specific OPC trials,” wrote C. Jillian Tsai, MD, PhD, of the Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York.

“Several de-escalation strategies for HPV–associated oropharyngeal carcinoma (OPC) have focused on deintensifying gross disease treatment. Reduction of radiotherapy dose and target volume to subclinical regions may achieve good clinical outcomes with favorable patient quality of life (QOL),” they added.

In this retrospective study, they sought to assess the effects of these changes, comprised of treating subclinical regions included in elective treatment volume (up to a dose of 30 Gy), and sparing selected negative neck, retropharyngeal, level 1b, and level V nodal basins.

In all, 276 patients (median age: 61 years; 89.5% men) with newly diagnosed HPV-positive oropharyngeal carcinoma who received CCRT with concurrent cisplatin or other chemotherapy from March 2017 to July 31, 2019, were included. Most (90.9%) were white, 66.3% had ˂10 pack-years of smoking, 23.5% had cN2-cN3 disease, and all had undergone excisional primary site or lymph node biopsy and had residual gross tumor burden after diagnostic biopsy.

Treatment was comprised of radiotherapy (30 Gy in 15 fractions) delivered to elective nodal and subclinical regions, followed by a cone down (40 Gy in 20 fractions; total dose: 70 Gy) to areas of gross disease.

Patients were followed typically every 3 months in the first year after CCRT completion, every 4-6 months during years 2 to 5, and annually thereafter. Patients also completed the Gothenburg Trismus Questionnaire (GTQ) at each visit, to assess jaw-related problems, limitations in eating, and muscular tension, and eight additional areas.

“The GTQ is a comprehensive, self-administered, trismus-specific questionnaire with different aspects of objective measures of 13 items and the following 3 domains: jaw-related problems, eating limitation, and muscular tension. There are an additional 8 single items,” explained the researchers.

Cisplatin therapy (300 mg/m2) was completed by 172 patients. During a median follow up of 26 months, eight developed locoregional recurrence (2.9%)—seven (87.5%) at the primary site or gross nodes treated with 70 Gy, and one with a persistent node not identified as gross disease treated with only 30 Gy. Importantly, no recurrence occurred in subclinical fields receiving a dose of 30 Gy or in the elective nodal regions that were omitted. In all, 6.9% of patients developed distant-only recurrence.

Upon multivariate Cox proportional hazards regression analyses, Tsai and co-authors found that only advanced N category was associated with worse locoregional control (HR: 3.4; 95% CI: 1.1-10.6; P=0.03). They found no differences in locoregional control between patients treated with high-dose cisplatin and weekly cisplatin or other chemotherapy combinations (HR: 0.8; 95% CI: 0.2-3.5; P=0.71).

“The only patient with treatment failure in the 30-Gy subclinical region received a cumulative cisplatin dose of a 300-mg/m2 bolus,” they noted.

Twenty-four-month locoregional control was 97%, progression-free survival 88.0%, distant metastasis-free survival 95.2%, and overall survival 95.1%.

Upon 24-month assessment of quality-of-life composite scores, including jaw-related problems, pain, social contact, eating, speech, and swallow, Tsai and co-authors found that most were comparable or better than baseline measures. This was not true, however, for senses, dry mouth, muscular tension, and cognitive functioning, which all improved over time but were still somewhat worse than at baseline.

Specifically, GTQ scores showed that all domain scores were worse 3 to 6 months after radiotherapy, but improved thereafter. By 24 months, all GTQ scores were comparable to baseline, except facial pain scores, which were “notably” better, improving from 12 at baseline to 7 at 24 months; and muscular tension scores, which stayed marginally worse, increasing from 9 at baseline to 13.

“In this retrospective cohort study with a median follow-up of 26 months, the systematic de-escalation of radiotherapy to 30 Gy with reduction of elective volumes irradiated was associated with minimal toxic effects. With longer term follow-up data to validate the results, this regimen can be safely adapted for treating a wide range of patients with HPV-associated OPC undergoing primary CCRT,” concluded Tsai and co-authors.

“In this issue of JAMA Oncology, Tsai and colleagues add to the literature with a thoughtful systematic investigation into elective dose de-intensification and volumetrically mediated harm minimization,” wrote Philip E. Schaner, MD, PhD, of the Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, and Ravi A. Chandra, MD, PhD, of the Oregon Health & Science University, Portland, Oregon in their accompanying editorial. “The synthesis of de-intensification and harm-minimization techniques used by Tsai and colleagues is supported by a growing body of literature implementing similar strategies.”

Nevertheless, many unknowns remain, they added, including how to select the best treatment option, and which patients can safely undergo de-escalation, and which would benefit from degrees of deintensification.

“The data from the study by Tsai and colleagues are encouraging but are still hypothesis-generating; the concept of substantially reducing elective dosing should be further integrated into prospective trial design,” concluded Schaner and Chandra.

Study limitations include that it was conducted at a single institution, was nonrandomized, and retrospective in nature.

Tsai and colleagues added: “Of note, 31.5% of the patients did receive an intermediate dose of 50 Gy for indeterminate nodes or other small areas of concern per the treating physician’s discretion, and this flexibility in dosing has worked well for treatment planning while still keeping most of the elective regions dosed to 30 Gy.”


This study was supported by grants from the National Institutes of Health and the NIH/National Cancer Institute (NCI).

Tsai reported receiving consultation fees from Varian Medical Systems outside the submitted work.

Schaner and Chandra reported no conflicts of interest.



Liz Meszaros, Deputy Managing Editor, BreakingMED™

Kaiser Health News

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.