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

NCT02918955 | Completed Phase 3 DMC

• 1 other identifier: BE 00733/16
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Head and Neck Neoplasms

Keywords

head and neck cancer; radiotherapy; chemotherapy; neck dissection; surgery; quality of life; toxicity; oropharyngeal cancer; laryngeal cancer; hypopharyngeal cancer

Outcome Measures

Primary Outcomes (1)

• Number of patients with acute & subacute toxicity based on CTCAE scoring system v4.03

  from the beginning of radiotherapy until 90 days after the end of the treatment

Secondary Outcomes (13)

• Number of patients with late Toxicity based on CTCAE scoring system v4.03

  beginning from 91 days after the end of radiotherapy until the end of the 2 years follow up

• Change from baseline quality of life(QoL)using EORTC QLQ-C30 v3&EORTC QLQ-H&N43 modules(Health related QoL specific for Head&Neck ca.)scores at end of RT, 3,12&24 months after RT.Swallowing (H&N43:4-item scale)3 months after RT is the primary QoL domain

  up to 24-28 months depending on the treatment duration.

• Loco-regional control

  2 years from the randomization

• Progression-free survival

  2 years from the randomization

• Overall survival

  2 years from the randomization

Study Arms (4)

Arm rA (randomized)

ACTIVE COMPARATOR

Concomitant chemo-radiotherapy with early salvage neck dissection if less than complete clinical response

Radiation: radiotherapy; Drug: Chemotherapy (Cisplatin); Procedure: Early Salvage Neck Dissection in case of less than cCR (Arm A only)

Arm rB (randomized)

EXPERIMENTAL

Up-front neck dissection followed by radiotherapy with concomitant chemotherapy based on the cT pN cM staging after surgery

Procedure: up-front neck dissection; Radiation: radiotherapy; Drug: Chemotherapy (Cisplatin)

Arm oA (non-randomized)

ACTIVE COMPARATOR

Concomitant chemo-radiotherapy with early salvage neck dissection if less than complete clinical response

Radiation: radiotherapy; Drug: Chemotherapy (Cisplatin); Procedure: Early Salvage Neck Dissection in case of less than cCR (Arm A only)

Arm oB (non-randomized)

EXPERIMENTAL

Up-front neck dissection followed by radiotherapy with concomitant chemotherapy based on the cT pN cM staging after surgery

Procedure: up-front neck dissection; Radiation: radiotherapy; Drug: Chemotherapy (Cisplatin)

Interventions

up-front neck dissection PROCEDURE

Arm oB (non-randomized); Arm rB (randomized)

radiotherapy RADIATION

70 Gy in 35 fractions to the macroscopic disease 50 Gy in 25 fractions (if sequential boost) or 56 Gy in 35 fractions (if simultaneous integrated boost) to the elective volumes 66 Gy in 35 fractions to the post-operative region with lymphatic extracapsular extension (Arm B only)

Arm oA (non-randomized); Arm oB (non-randomized); Arm rA (randomized); Arm rB (randomized)

Chemotherapy (Cisplatin) DRUG

100 mg/m2 every three weeks during radiotherapy In Arm B, chemotherapy can be omitted in case of a cT1-2 primary and a surgical downstaged pN0-1 neck without lymphatic extracapsular extension.

Arm oA (non-randomized); Arm oB (non-randomized); Arm rA (randomized); Arm rB (randomized)

Early Salvage Neck Dissection in case of less than cCR (Arm A only) PROCEDURE

Early salvage neck dissection in case of residual lymph node disease will be performed based on the response evaluation by MRI and PET/CT performed 3 and 4 months after the end of (chemo)radiotherapy, respectively (and additional diagnostic modalities if clinically indicated by the physician) and not more than 3 weeks after this post-radiotherapy evaluation. In Arm A, a successful early salvage neck dissection without the operation of the primary tumor in case of less than clinical complete response (cCR) will be considered a component of the multimodality treatment and not as a failure.

Arm oA (non-randomized); Arm rA (randomized)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead
• University of Bern: collaborator

Study Sites (2)

Inselspital Bern

Bern, 3010, Switzerland

Location

University Hospital of Geneva

Geneva, 1205, Switzerland

Location

MeSH Terms

Conditions

Head and Neck Neoplasms; Oropharyngeal Neoplasms; Laryngeal Neoplasms; Hypopharyngeal Neoplasms

Interventions

Radiotherapy; Drug Therapy; Cisplatin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Laryngeal Diseases; Respiratory Tract Diseases; Respiratory Tract Neoplasms

Intervention Hierarchy (Ancestors)

Therapeutics; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Study Officials

• Olgun Elicin, MD

  Department of Radiation Oncology, Inselspital

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2016
• First Posted: September 29, 2016
• Study Start: December 16, 2016
• Primary Completion: June 24, 2025
• Study Completion: June 24, 2025
• Last Updated: November 20, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

CH (2)