The trial evaluates the value of radiation dose escalation based on Hypoxia detection by 18F_misonidazole Positron Emission Tomography (18F-MISO-PET) for primary radiochemotherapy of head and neck squamous cell carcinoma. Patients negative for human papillomavirus (HPV) and with hypoxic tumours after 2 weeks of radiochemotherapy are randomized to completion of standard radiochemotherapy or radiochemotherapy with escalated radiation dose. An additional interventional arm includes a carbon ion boost. HPV positive tumours can be included in a control arm. Primary endpoint is local tumour control 2 years after radiochemotherapy.

Previous preclinical data and a prospective validated patient cohort have shown that patients with head and neck squamous cell carcinoma, whose tumours are hypoxic after 2 weeks of primary radiochmeotherapy, have a significantly lower chance of locoregional tumour control. The multi-center trial evaluates the value of radiation dose escalation based on hypoxia detection by 18F_misonidazole Positron Emission Tomography (18F-MISO-PET) for primary radiochemotherapy of head and neck squamous cell carcinoma. Patients negative for human papillomavirus (HPV) and with hypoxic tumours after 2 weeks of radiochemotherapy are randomized to completion of standard radiochemotherapy (70 Gy) or radiochemotherapy with escalated radiation dose (77 Gy). An additional interventional arm includes a carbon ion boost to 77 Gy. HPV positive tumours can be included in a control arm. Primary endpoint is local tumour control 2 years after radiochemotherapy. Secondary endpoints include acute and late toxicity (CTCAE 5.0), regional tumor control, overall survival, disease free survival, distant metastases, kinetics analysis of dynamic FMISO-PET scans, Quality of life (QoL). The hypothesis is that local tumour control 2 years after radiochemotherapy is higher in the dose escalated compared to the control arm.

Inclusion Criteria:

• Age: older than 18 years
• WHO (ECOG) performance status 0-2
• Histological proven HNSCC
• HPV negative tumors or HPV positive tumors
• Stage III, IVA or IVB HNSCC according to UICC and AJCC guidelines
• Tumor classified as irresectable or patient inoperable or patient refused surgery
• Tumor extension and localization suitable for radiochemotherapy with curative intent
• Simultaneous standard chemotherapy with cisplatin applicable (no contra-indications)
• Dental examination and -treatment before start of therapy
• For women with childbearing potential and men in reproductive ages adequate contraception.
• Ability of subject to understand character and individual consequences of the clinical trial
• Written informed consent (must be available before enrolment in the trial)

Exclusion Criteria:

• Refusal of the patients to take part in the trial
• Presence of distant metastases (UICC stage IVC)
• Previous radiotherapy in the head and neck region
• Second malignancy that is likely to require treatment during the trial intervention or follow-up period or that, in the opinion of the physician, has a considerable risk of recurrence or metastases within the follow-up period
• Serious disease or medical condition with life expectancy of less than one year
• Participation in competing interventional trial on cancer treatment
• Patients who are not suitable for radiochemotherapy
• Pregnant or lactating women
• Patients not able to understand the character and individual consequences of the trial
• Nasopharyngeal Carcinomas