Around 30–50% of patients with locally advanced head and neck cancer (HNC) develop local recurrence or tumor progression after initial multimodal therapy [
1,
2]. Local tumor growth can lead to severe symptoms such as dysphagia, cachexia, and tumor pain with a significant decrease of the quality of life (QoL). The therapeutic options are limited in this highly pre-treated, vulnerable patient cohort. Depending on the tumor localization, salvage surgery should be evaluated in patients with good performance status with a 2-year progression-free survival around 70% for stage I/II and 30% for stage III rHNC [
3]. However, only a subset of patients (approximately 30–50%) is suitable for a salvage surgery in the clinical routine. Palliative systemic therapies showed limited positive effects with the “EXTREME” regimen resulting in overall survival (OS) rates of 10.1 months and around 80% severe treatment toxicity (≥grade III) [
4]. Recently, immunotherapy has emerged as a treatment option for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) [
5].
The clinical routine for reirradiation of rHNC is reIMRT [
6,
7]. Definitive reIMRT is commonly applied with a total dose up to 60 Gy in 2 Gy fractions [
8]. In this heavily pretreated patient cohort, reIMRT was associated with unfavorable rates of treatment-related toxicity (≥grade III) in 30–40% of patients [
8‐
10]. The combination treatment of chemotherapy with photon reirradiation further intensified severe toxicities [
6,
7] but showed unfavorable 2-year OS rates ranging from 15 to 26% in patients with rHNC. Stereotactic body radiation therapy (SBRT) has emerged as a viable therapeutic option for non-resectable rHNC with the potential to significantly reduce acute and chronic treatment associated toxicity [
11,
12]. However, the clinical benefit of reirradiation with SBRT compared to reIMRT has yet to be demonstrated in a prospective clinical trial. High total doses from previous irradiation treatment generally limit the dose of reirradiation. The relative biological effectiveness (RBE) of carbon ions is higher compared to photons and it is associated with favorable effects in radioresistant tumors [
13]. Because of the steep dose gradient, reCIRT is superior in sparing normal tissue and organs at risk, compared to reirradiation with photons. Consequently, carbon ions possibly represent a feasible and effective treatment modality for salvage reirradiation. A retrospective analysis on 229 consecutive patients with rHNC treated at our clinic with reCIRT showed encouraging results with 3.1% acute and 14.5% late severe (≥grade III) toxicity [
14]. A median total dose of 51 Gy (RBE) in 17 fractions of 3 Gy (RBE) was safe and effective for reCIRT with a median OS of 13.7 months for patients with recurrent HNSCC. Data on reCIRT in patients with rHNC is rare, especially in the prospective setting. In the current CARE trial, the impact of reCIRT or reIMRT will be evaluated and the toxicity/safety and efficacy will be compared.