Personalized Elective Neck Irradiation Guided by Sentinel Lymph Node Biopsy in Larynx and Pharynx Cancer. The PRIMO Study.

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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 nodal metastases that are under the diagnostic detection level. 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 elective 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 in the majority of patients with a clinically negative neck because occult nodal metastases are present approximately in 3 out of 10. This will enable better sparing of normal tissues from radiation and consequentially result in less permanent long-term radiation side effects with better quality of life after treatment.

Objective \| To compare safety and efficacy of treatment with sentinel lymph node biopsy guided elective 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 personalized elective 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 new standard of care.

Population \| Patients to be treated with definitive (chemo)radiotherapy for stage cT1-4N0M0 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. 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 only (if a sentinel lymph node is positive at one side of the neck) or bilateral (if sentinel lymph nodes are positive at both sides of the neck). For patients randomized to the control arm sentinel lymph node biopsy will not be performed and all will receive standard bilateral elective neck irradiation.

Primary endpoints \| The primary safety endpoint is the number of patients with recurrence in regional lymph nodes (in the absence of synchronous recurrence of the primary tumor or second primary tumor) within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life measured by the xerostomia symptom scale of the EORTC QLQ-H\&N35 at 6 months after treatment.

Other endpoints \| Acute and late radiation toxicity, quality of life after treatment with focus on xerostomia and dysphagia, local and regional control rates, disease specific and overall survival, and cost-effectiveness.

Burden associated with participation \| Patients randomized to the intervention arm will undergo sentinel lymph node biopsy (flexible endoscopic tracer injection under topical anesthesia in the outpatient clinic, SPECT/CT-scan and surgical removal of identified sentinel lymph nodes under general anesthesia). These procedures will not be performed in patients in the control arm. For patients randomized to the intervention arm there is a potential increased risk for regional recurrence because elective neck irradiation is omitted based on the histopathologic status of the sentinel lymph node(s). However this risk is expected to be very small (3.1% versus 2.0% in the control arm). Because regional recurrences can be cured in 70-90% of the patients with salvage neck dissection, the effect on overall survival is expected to be negligible. Independent of randomization, participants will undergo non-invasive procedures to objectify radiation sequelae and will be asked to complete quality of life questionnaires.

Benefit associated with participation \| With sentinel lymph node biopsy, it is expected that futile elective neck irradiation can be omitted to one or both sides of the neck in 9 out of 10 patients. This will enable better sparing of normal tissues from radiation and it is expected that this will result in a major decrease of permanent long-term radiation side effects (such as xerostomia and dysphagia) with better quality of life after treatment compared to standard elective neck irradiation.

Eligibility Criteria:
Inclusion Criteria:

* Adult patients (≥18 years) with newly diagnosed cT1-4N0M0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx.
* Histopathological diagnosis of squamous cell carcinoma in the primary tumor.
* Adequate staging of the neck including CT or MRI, and 18F-FDG-PET demonstrating cN0
* Recommendation for curative intent external beam (chemo)radiotherapy made by a multidisciplinary head and neck oncology team (in case of chemoradiotherapy, only patients receiving concomitant platinum-based regimen are eligible).
* Bilateral elective neck irradiation is indicated according to Dutch consensus guidelines (LPHHRT)
* Procedures for sentinel lymph node biopsy (i.e. tumor accessible for tracer injection, imaging and surgery under general anesthesia) are deemed feasible by the head and neck surgeon.

Exclusion Criteria:

* Recurrent disease or previous anticancer treatment to the head and neck area (e.g. radical attempt or tumor reductive surgery, neck dissection, neo-adjuvant chemotherapy or radiotherapy) except for endoscopic glottic laser micro surgery.
* Well lateralized oropharyngeal cancers and early stage laryngeal cancers requiring no or unilateral elective neck irradiation according to Dutch consensus guidelines (LPHHRT).
* Patients that qualify for proton therapy and want to be treated accordingly.
* Compromised airway or tracheostomy.
* Any active invasive malignancy within the last 3 years except for early stage basal/squamous cell carcinoma of the skin and incidental finding of stage T1N0M0 prostate cancer.
* Any somatic, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol or follow-up schedule.