AUTHOR=Haderlein Marlen , von der Grün Jens , Balermpas Panagiotis , Rödel Claus , Hautmann Matthias G. , Steger Felix , Bohr Christopher , Hehr Thomas , Stromberger Carmen , Budach Volker , Schymalla Markus , Engenhart-Cabillic Rita , Kocik Lukas , Geinitz Hans , Nestle Ursula , Klautke Gunter , Scherl Claudia , Gall Christine , Frey Benjamin , Schubert Philipp , Semrau Sabine , Ott Oliver , Kesting Marco , Iro Heinrich , Mueller Sarina K. , Fietkau Rainer 

TITLE=De-intensification of postoperative radiotherapy in head and neck cancer irrespective of human papillomavirus status—results of a prospective multicenter phase II trial (DIREKHT Trial)

JOURNAL=Frontiers in Oncology

VOLUME=Volume 14 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1447123

DOI=10.3389/fonc.2024.1447123

ISSN=2234-943X

ABSTRACT=Background
Current standard treatment concepts in head and neck squamous cell carcinoma (HNSCC) are based on former studies using 2D and 3D treatment plans. However, modern radiation techniques allow for a more precise and individual dose application.  Therefore, in a clearly defined patient population de-intensified risk-adapted radiation is investigated.

Methods
Patients with newly diagnosed HNSCC after surgery(with resection margins≥1mm and cM0) with the following tumor stages (TNM 7thEdition) were eligible for the study: Oral cavity, oropharynx or larynx: pT1-3, pN0-pN2b, hypopharynx: pT1-2; pN1. The patients should either have a low risk of local recurrence(≤pT2, resection margin ≥5mm, no peritumoral lymphangiosis(L0) and no perineural invasion)
 or contralateral lymph node metastasis (≤ 3 ipsilateral lymph node metastases, in case of well-lateralized oropharyngeal or oral cavity cancer contralateral cN0, otherwise pN0).
Patients were assigned to 3 different treatment regimes with reduction of the treated volume, radiation dose or both, according to tumor stage and results of surgery performed(see Fig1). 
Primary objective was to show LRR of <10% after 2years.

Findings:
150 patients were enrolled. Tumor localisations were: n=53(35·3%) oral cavity, n=94(62·7%) oropharynx (82% HPV-positive), n=2(1·3%) Hypopharynx, n=1(0·7%) Larynx. 61 patients(41·0%) were stage IVA, 81(54·0%) stage III and 8(5·3%) stage II. 
Median follow up was 36 months. Cumulative incidence of 2y-LRR was 5·6%(95% CI: 1·7%-9·2%) in the whole study population and 14.1%(95%CI: 3.8%-23.2%) in patients with oral cavity cancer. 
Cumulative incidence of 2y-LRR in non-irradiated or dose-reduced regions was 3·5 %(95% CI: 0·4%-6·5%)
After 2 years disease-free survival was 92%(95% CI: 87%-96%), overall survival was 94%(95% CI: 90%-98%) for the complete study cohort.
Acute III° toxicity was as follows: dysphagia: 30%, xerostomia: 7%, mucositis 19%, dermatitis: 4%.Dysphagia and xerostomia decreases over time. After 27 months late dysphagia III° and xerostomia II° was 1% and 9%.

Interpretation:
The study met its primary objective. De-intensification of postoperative radiotherapy irrespective to HPV status in a pre-defined patient population is associated with a favorable toxicity profile without compromising LRR. In an unplanned subgroup analysis, a significantly increased risk of LRR was observed in patients with oral cavity cancer. In these patients, deintensified radiotherapy should be applied with caution.