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

Treatment of regionally-advanced head and neck squamous cell carcinoma (HNSCC) requires a multidisciplinary approach with a combination of surgery, radiotherapy (RT) and chemotherapy. Due to these aggressive combined modalities, patients undergoing treatment and many survivors develop toxicities which impact quality of life (QoL) and sometimes lead to mortality.

Lymph node metastases of HNSCC are frequent and considered one of the most important prognostic factors, resulting in decreased survival by 50%. More than three decades, the optimal management strategy of node positive HNSCC was a key subject of debate. In summary, the current literature provides us two important findings: First, with the contemporary imaging and treatment modalities, there is no role of a planned neck dissection (ND) added to (chemo)radiotherapy ((C)RT) in terms of oncological outcome and survival. Second, with modern RT techniques, a tailored treatment followed after an up-front neck dissection (UFND) allows a significant reduction of treatment volumes and de-escalation of the dose to the neck, leading to reduction of treatment related toxicities.

In this study strategies with and without up-front neck dissection prior to chemo-radiotherapy will be compared.

The main objective of this project is to test the hypothesis that the addition of UFND prior to (C)RT results in a significant reduction of treatment toxicities and improvement of QoL in regionally advanced (cN2-3) HNSCC through dose de-escalation and volume reduction of RT.

The primary endpoint of this trial is to evaluate the toxicity from the beginning of radiotherapy until 90 days after the end of the treatment. The incidence of acute and subacute toxicities higher than grade ≥3 (CTCAE v.4, except for Xerostomia, for which RTOG/EORTC scale will be used) will be compared between study arms. Secondary endpoints include the survival endpoints for both treatment modalities; i.e. loco-regional control, progression-free and overall survival. Assessment of QoL (EORTC QLQ-C30 + H\&N43), late toxicity, surgical complications, cost-effectiveness and the need of feeding-tube will be a part of the final analysis of this trial.

Trial design: randomized multi-center open-label comparative one-staged phase III trial with a superiority design and the primary endpoint of highest grade radiation toxicity during and until 90 days after the completion of the treatment. Interventions in both arms of the trial are considered as standard treatments. No experimental diagnostic tools will be used during the trial. In addition to the randomized arms, two identical observational arms will be opened for the patients who are diagnosed before the activation of the randomized arms, and subsequently for those who refuse to be randomized. Their aim is to prospectively acquire high quality data for patients who refuse randomization. The observational and randomized cohorts will be analyzed separately for the pre-defined endpoints.

For the calculation of the sample size, grade ≥3 acute radiation toxicity in the CRT alone (Arm A) was assumed as 70% based on literature. For the primary endpoint, a follow-up period of 90 days after the last day of (C)RT is needed after the accrual of the last patient. However, 2 years of follow-up after (C)RT is needed for the secondary endpoints (exception: oncological outcome and survival will be calculated from the day of randomization in order to avoid immortal time bias). On this basis, sample size was calculated based on the Pearson chi-squared test and performed in Stata. Assuming a toxicity fraction of 70% for any grade 3 or higher toxicity in Arm A, a relative risk of 0.5 (35% in Arm B), a two-sided alpha of 0.05, a power of 80%, a drop-out rate of 5%, and an allocation ratio of 1 we calculated an overall sample size of 65. Expected accrual time is 3 years.

Eligibility Criteria:
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.