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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

242 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-12-06

Study Completion Date

2029-12-01

Brief Summary

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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.

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Detailed Description

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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 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).

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 initially clinically positive nodes, 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 most 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.

Conditions

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Laryngeal Squamous Cell Carcinoma Hypopharynx Squamous Cell Carcinoma Oropharyngeal Squamous Cell Carcinoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Sentinel lymph node biopsy guided selective elective neck irradiation

* Sentinel lymph node biopsy
* Radiotherapy (IMRT/VMAT with SIB) to the primary tumor with selective elective neck irradiation guided by histopathologic status of the sentinel lymph node(s)

Group Type EXPERIMENTAL

Sentinel lymph node biopsy guided selective elective neck irradiation

Intervention Type RADIATION

Patients will undergo sentinel lymph node biopsy. Based on the histopathologic status of the sentinel lymph node(s), selective elective neck irradiation is performed with standard radiation treatment of the primary tumor.

There are 3 possible treatment scenarios.

1. Bilateral elective neck irradiation is indicated when lymph nodes at both sides of the neck contain metastases or when sentinel lymph node detection fails.
2. Unilateral elective neck irradiation is indicated when lymph nodes at one side of the neck only contain metastases.
3. Full omission of elective neck irradiation is indicated when lymph nodes at both sides of the neck are free of metastases.

Standard elective neck irradiation

\- Radiotherapy (IMRT/VMAT with SIB) to the primary tumor with standard bilateral elective neck irradiation

Group Type ACTIVE_COMPARATOR

Standard elective neck irradiation

* 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.

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No