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.
Trial Snapshot
- Phase
- Phase 3
- Status
- Recruiting
- Enrollment
- 242
- Locations
- 11
- Primary Endpoint
- Patiënt reported xerostomia related quality of life as assessed by EORTC Quality of Life Questionnaire Head and Neck Module (QLQ-H&N35)
Study Overview
Brief Summary
Rationale | Elective neck irradiation is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy. 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.
Methods/design | This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with sentinel lymph node biopsy guided neck irradiation versus standard bilateral elective neck irradiation in 242 patients with cN0-N2b squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral elective neck irradiation is indicated. Patients randomized to the experimental-arm will undergo sentinel lymph node biopsy. Based on the histopathologic status of the sentinel lymph nodes, patients will receive no elective neck irradiation (if no nodal metastases found at both sides of the neck), unilateral neck irradiation only (if no nodal metastases found at contralateral side of the neck only) or bilateral neck irradiation (if nodal metastases found at both sides of the neck). Patients randomized to the control arm will not undergo sentinel lymph node biopsy but will receive standard bilateral elective neck irradiation. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment.
Discussion | If this trial demonstrates that the experimental 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.
Detailed Description
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).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Adult patients (≥18 years) with newly diagnosed cT1-4N0-2bM0 squamous cell carcinoma of the oropharynx (HPV-), larynx or hypopharynx, or cT1-4N0-1M0 oropharynx (HPV+) (AJCC TNM 8)
- •Histopathological diagnosis of squamous cell carcinoma.
- •Adequate staging of the neck including CT or MRI, and 18F-FDG-PET demonstrating no contralateral lymph node metastases.
- •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 ENI is indicated according to Dutch consensus guidelines (LPHHRT) (see Appendix 13.1).
- •Procedures for SLNB (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 ENI according to Dutch consensus guidelines (LPHHRT)
- •Patients receiving concomitant non-platinum-based systemic agents (e.g. cetuximab).
- •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.
Outcomes
Primary Outcomes
Patiënt reported xerostomia related quality of life as assessed by EORTC Quality of Life Questionnaire Head and Neck Module (QLQ-H&N35)
Time Frame: 6 months
Number of patients with regional recurrence
Time Frame: 24 months
Only recurrence in regional lymph nodes in the absence of synchronous recurrence of the primary tumor or initially clinically positive nodes, or second primary head and neck tumors are considered as events
Patiënt reported xerostomia related quality of life as assessed by EORTC Quality of Life Questionnaire Head and Neck Module (QLQ-H&N35)
Time Frame: 6 months
Secondary Outcomes
No secondary outcomes reported