Hypoxia occurs in about 80% of head and neck tumors. Based on experimental and clinical data, hypoxia is a useful parameter for pretherapeutic stratification. These radioresistant regions can be detected with FMISO PET/CT. Moreover, hypoxic subvolumes of tumors can be evolving as target volumes for radiotherapy ("dose painting") in hypoxia imaging-based dose escalation.

The radiotherapy protocol will include two dose-escalation regimens. The dose in hypoxic tumor volume will be escalated either by conventional RT or stereotactic radiotherapy technique. Concurrent chemotherapy cisplatin will be administered weekly 35-40 mg/m2 or every three weeks 80-100 mg/m2. The parameter of cumulative cisplatin dose of 200 mg/m2 during the whole course of radiotherapy will be also taken into account. Patients will be examined and monitored at least every two weeks.

Target volumes and dose and fractionation:

Definition of gross tumor volumes (GTV), clinical target volumes (CTV) and planning target volumes (PTV) will follow recommendations of DAHANCA, EORTC and RTOG guidelines.

The conventional radiotherapy protocol:

Standard fractionation regimen: 70 Gy/54 Gy in 33 fractions GTV primary - CTV - PTV (5+5mm): for dose 70 Gy in 33 fractions GTV LN bulky (> 3cm) - PTV (5mm): for dose 70 Gy in 33 fractions LN low risk (for elective irradiation) - CTV - PTV (3mm-5mm): for dose 54 Gy in 33 fractions

Dose escalated radiotherapy protocol:

Dose escalated radiotherapy protocol: 75,9 - 79,2 Gy in 33 fractions GTV hypoxic or any hypoxic LN > 2cm - PTV (0mm): dose 75,9 - 79,2 Gy in 33 fractions (Contours must be subtracted and reduce by 3mm in case of close relation to the skin, bones or large blood vessels) GTV primary - CTV - PTV (5+5mm): for dose 70 Gy in 33 fractions LN low risk (for elective irradiation) - CTV - PTV (3mm-5mm): for dose 54 Gy in 33 fractions

Inclusion Criteria:

• Pathologically proven new diagnosis of oropharyngeal p16 negative, or laryngeal, hypopharyngeal, oral cavity (independent of p16) squamous cell carcinoma of clinical stage III, IV confined to head and neck area
• Evaluable tumor burden assessed by computed tomography scan or magnetic resonance imaging, based on RECIST (Response Evaluation Criteria in Solid Tumours) version 1.1
• Eligibiity for definitive chemoradiation or hyperfractionated accelerated radiotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate kidney and liver function

Exclusion Criteria:

• Prior surgical treatment - any surgery of primary tumor or involved nodes or prior surgical debulking apart from surgery with diagnostic intention (e.g. open biopsy if necessary)
• Prior systemic therapy, targeted therapy, radiotherapy treatment for head and neck cancer
• Cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or unknown primary head and neck cancer
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis or any distant metastasis
• Known active Hepatitis B or C
• History of Human Immunodeficiency Virus (HIV)
• History of a diagnosed and/or treated hematologic or primary solid tumor malignancy, unless in remission for at least 5 years prior to randomization
• Previous allogeneic tissue/solid organ transplant
• Active infection requiring systemic therapy