Definitive Chemo-Radiotherapy for Regionally Advanced Head and Neck Cancer With or Without Up-front Neck Dissection

1. Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
2. Patient should not be a participant in any interventional clinical trial.
3. Age ≥ 18 years.
4. WHO/ECOG performance status 0-2 within 28 days prior registration.
5. Histopathologically confirmed, previously untreated HNSCC of the oropharynx, hypopharynx or larynx within 6 weeks (42 days) of registration.
6. No cT4 primary tumor destructing and/or breaching through bone and/or cartilage (cortical invasion only is still eligible).
7. Clinical Nodal stage (cN) of at least cN1.
8. No evidence of distant metastases (cM0). No synchronous second primary HNSCC at the time of diagnosis.
9. No synchronous or previous malignancies. Exceptions are adequately treated basal cell carcinoma or SCC of the skin, or in situ carcinoma of the cervix uteri or breast with a cancer-free follow-up time of at least 3 years, or other previous malignancy with a disease-free interval of at least 5 years.
10. No prior radiotherapy to the head and neck region (or any RT fields/volumes which may overlap with the intended therapy volumes).
11. No prior neck dissection or single lymph node excision is allowed.
12. History and physical examination by treating physician (head and neck surgeon, medical oncologist or radiation oncologist) within 28 days prior registration.
13. Patients must have clinically and/or radiological documented measurable disease. At least one site of disease must be unidimensionally measurable as per RECIST 1.1. All imaging studies for staging must be performed within 28 days prior to registration.
14. Imaging of the head and neck (CT with contrast, PET/CT and/or MRI) within 28 days prior to registration: A CT scan (as part of the PET/CT is also accepted), with contrast is mandatory unless contraindicated (e.g. contrast allergy, renal insufficiency etc.). Note that a PET/CT scan alone, unless performed with radio-opaque contrast material is not sufficient for the CT-based evaluation of the head and neck area.
15. PET/CT of the whole body within 28 days prior registration
16. QoL and toxicity evaluation completed within 28 days or at the time of registration. Exceptions: 1) Language problems or any health problems interfering with the QoL assessment. 2) Patients who want to be enrolled into the observational arms and refuse to take part in the QoL assessments.
17. Patients with a contraindication against neck dissection are not eligible (e.g. medical co-morbidities, positive lymph node conglomerates enclosing and infiltrating carotid artery or merging with the primary tumor)
18. The patient must be expected to withstand neck dissection and radiotherapy combined with cisplatin.
19. Preservation of the accessory nerve during neck dissection should be possible. Patients expected to have a permanent shoulder dysfunction because of a planned sacrifice of the accessory nerve are not eligible.
20. Laboratory requirements within 28 days prior to accrual:

    1. Adequate renal function: Serum creatinine ≤1.5 mg/dL and/or creatinine clearance \>50 mL/min estimated within 28 days prior accrual
    2. Absolute neutrophil count (ANC) ≥1.0 x 109/L
    3. Platelet count ≥75 x 109/L
    4. Hemoglobin ≥10 g/dL or 6.2 mmol/L (Note: The use of transfusion to achieve Hgb ≥10 g/dL is acceptable)
    5. Bilirubin \<1.5 times of upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<3 times of ULN.
21. Women are not breastfeeding. Women with Child-bearing potential and using effective contraception (see Section 5.6), and not pregnant and agree not to become pregnant during participation in the trial and 2 years after chemoradiotherapy. A negative pregnancy test before inclusion (within 28 days) into the trial is required for all women with child-bearing potential. Men agree not to father a child during participation in the trial and 2 years after chemoradiotherapy.
22. No allergy to study drugs or to the excipients in their formulation.
23. No peripheral neuropathy ≥grade 2 according to CTCAE v4.03 (grade 2 = moderate symptoms limiting instrumental ADL)
24. No co-existing disease prejudicing survival (expected survival \<6 months).
25. No severe cardiac illness: Myocardial infarction within 6 months prior to randomization, severe congestive heart failure, severe cardiomyopathy, ventricular arrhythmia, unstable angina, uncontrolled hypertension.
26. No active bacterial or fungal infection requiring intravenous antibiotics at the time of registration
27. No Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 28 days before registration.
28. No hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
29. No clinically manifested Acquired Immune Deficiency Syndrome (AIDS) or immune-compromised patients. Note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.