Personalized Elective Neck Irradiation Guided by Sentinel Lymph Node Biopsy in Patients With Squamous Cell Carcinoma of the Oropharynx, Larynx or Hypopharynx With a Clinically Negative Neck: (Chemo)Radiotherapy to the PRIMary Tumor Only. The PRIMO Study.

Rationale | Squamous cell carcinoma of the upper aerodigestive tract comes with a substantial risk for cervical lymph node metastases. Elective neck irradiation is performed in patients receiving (chemo)radiotherapy aiming to eradicate eventual nodal metastases that are under the detection level of pretreatment imaging techniques. Most toxicity and permanent long-term radiation side effects are caused by elective neck irradiation. In particular xerostomia and dysphagia are notoriously known to negatively and permanently affect quality of life. Sentinel lymph node biopsy has emerged as a staging procedure that can reliably detect microscopic metastases by histopathological examination of sentinel lymph nodes and the pathologic status of the sentinel lymph node accurately reflects the status of the remaining nodal basin. A recent meta-analysis demonstrated an excellent diagnostic test accuracy of sentinel lymph node biopsy in patients with cancer of the oropharynx, larynx and hypopharynx (sensitivity 0.93 and negative predictive value 0.97). It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy. With this approach it is expected that elective neck irradiation can be omitted to one or both sides of the neck in 9 out of 10 patients with a clinically negative neck (cN0). For patients with clinically positive ipsilateral nodes (cN1-2b), it is expected that elective irradiation of the contralateral neck can be omitted in 7 out of 10 patients. This will enable better sparing of normal tissues from radiation and result in less permanent long-term radiation side effects with better quality of life.

Objective | To compare safety and efficacy of treatment with sentinel lymph node biopsy guided neck irradiation versus standard elective neck irradiation in patients receiving definitive (chemo)radiotherapy for squamous cell carcinoma of the oropharynx, larynx or hypopharynx.

Design | This is a multicenter, randomized controlled trial. In total 242 patients will be randomized in ratio 1:1 to the control arm with standard bilateral elective neck irradiation or to the interventional arm with sentinel lymph node biopsy guided neck irradiation. During a 2 year follow-up, data on toxicity, quality of life and oncologic outcomes will be collected. If this trial demonstrates that the interventional treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the standard of care.

Population | Patients to be treated with definitive (chemo)radiotherapy for stage cT1-4N0-2bM0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral elective neck irradiation is indicated. Excluded are patients with recurrent disease or patients who received previous oncologic surgery or radiotherapy to the neck.

Intervention | Patients randomized to the intervention arm will undergo sentinel lymph node biopsy. For patients with a clinically negative neck (cN0), sentinel lymph node biopsy is performed bilaterally. Based on the histopathologic status of the sentinel lymph node(s), patients will receive no elective neck irradiation (if all sentinel lymph nodes are negative), unilateral neck irradiation only (if a sentinel lymph node is positive at one side of the neck) or bilateral neck irradiation (if sentinel lymph nodes are positive at both sides of the neck). For patients with clinically positive ipsilateral nodes (cN1-2b), sentinel lymph node biopsy is performed contralaterally only. Contralateral elective neck irradiation will only be performed when sentinel lymph nodes are positive. For patients randomized to the control arm sentinel lymph node biopsy will not be performed and all will receive standard bilateral elective neck irradiation (with boost to clinically positive ipsilateral nodes (cN1-2b) if present).