Surgery and Reducing Ionizing Radiation of the Unknown Primary

Approximately 3% of all head and neck squamous cell carcinoma (SCC) patients present with nodal disease from an unknown primary (PUK). The incidence of PUK has increased in tandem with the rise of human papillomavirus (HPV)-mediated oropharyngeal SCC (OPSCC). HPV-mediated PUK now represents at least half of the head and neck PUK population, with an excellent prognosis and approximately 90% 5-year overall survival (OS).

The work-up for PUK has significantly improved with the introduction of positron emission tomography (PET) imaging and transoral robotic surgery (TORS). PET identifies at least 40% of primaries in PUK patients when clinical and radiological work-up is negative, and TORS has a higher primary identification rate (70%-80%). Current guidelines recommend tonsillectomy and tongue base mucosectomy in the work-up of PUK patients.

Definitive management of HPV-mediated PUK remains controversial, with curative options including primary neck dissection ± adjuvant therapy or primary radiotherapy ± concurrent chemotherapy. Treatment morbidity is significant, despite the excellent outcomes (90% 5-year OS). Key issues include the choice of initial treatment modality and whether to treat mucosal surfaces with radiation prophylactically.

Current guidelines recommend single-modality surgery (neck dissection) for low-volume neck disease. This recommendation is based on studies suggesting low primary emergence rates (1.5%-7%) and outcomes comparable to non-surgical treatment paradigms. Evidence from early-stage OPSCC supports surgery alone as a safe option for HPV-mediated PUK.

A critical question is whether to irradiate mucosal surfaces when using radiotherapy for HPV-mediated PUK. Emerging data suggest that omitting mucosal radiation has a very low risk (\<5%) of primary tumour emergence, potentially improving long-term quality of life and reducing toxicities like dysphagia and xerostomia. Several retrospective studies support the safety and reduced toxicity of involved neck radiotherapy without mucosal irradiation.

This trial is specifically designed with an upfront neck dissection alongside tonsillectomy and tongue base mucosectomy. Combining an upfront therapeutic neck dissection with the final stage of the diagnostic work-up has several benefits. Surgically treating the neck in selected patients during tonsillectomy and tongue base mucosectomy accelerates treatment, avoids additional delays, reduces costs to healthcare institutions, and prevents the need for a second surgery if no primary is identified. The addition of neck dissection to tonsillectomy and tongue base mucosectomy also involves relatively minor additional surgical morbidity in the context of a patient already undergoing pharyngeal surgery. In some instances, upfront surgical treatment of the neck may complete definitive treatment at the earliest opportunity. Patients with intermediate-volume neck disease, who require dual-modality treatment, also benefit from no further surgical delay and can proceed to radiotherapy following a single surgical encounter. An upfront neck dissection is also the gold standard for lymph node evaluation and may down-stage patients into a unimodality approach, thereby avoiding additional toxicity. For example, if imaging suggests multiple involved ipsilateral nodes in an HPV-mediated PUK patient, conventional treatment would involve dual-modality therapy. Pathological staging may down-stage this patient into a unimodality paradigm, sparing them significant toxicity.

In this randomized phase II trial, the study team hypothesizes that omitting mucosal radiation will lead to improved quality of life, decreased toxicity, and low rates of primary tumour emergence. Further, the researchers hypothesize that neck dissection alone for low-volume HPV-mediated PUK will result in excellent oncologic and functional outcomes.

The main objective is to assess the impact of omitting mucosal radiation on oncologic outcomes, toxicity, functional outcomes, and quality of life (QOL) in patients with p16-positive PUK.

The primary endpoint is to determine the rate of primary emergence of a mucosal p16-positive SCC in the upper aerodigestive tract compared to historical controls.

The secondary endpoints include:

Quality of life (using MDADI, EORTC QLQ-C30 and H\&N35, EQ-5D-5L, NDII) Overall survival (OS) Disease-free survival Regional recurrence within the neck Distant recurrence outside the upper aerodigestive tract and neck levels Rate of salvage treatment for primary emergence Rate of unsalvageable primary emergence Rate of percutaneous feeding tube insertion and use at 1 year Swallowing function (DIGEST score, FOIS) Toxicity (CTCAE version 5) Patients will be randomized 1:2 between the standard of care (Arm 1) and omission of radiation to mucosal surfaces (Arm 2).

Combining neck dissection with tonsillectomy and tongue base mucosectomy accelerates treatment, reduces costs, and avoids additional surgery. This approach involves minor additional surgical morbidity and can complete definitive treatment at the earliest opportunity. Upfront neck dissection also allows for accurate lymph node evaluation and potential down-staging, thereby sparing patients from additional toxicity.

The SUPERIOR trial aims to determine whether omitting mucosal radiation improves quality of life and reduces toxicity in HPV-mediated PUK patients, while evaluating the efficacy of neck dissection alone for low-volume disease. The study seeks to establish evidence-based guidelines for the optimal management of HPV-mediated PUK.

• MD Anderson Dysphagia Inventory (MDADI) [Срок оценки: Assessed at baseline, 6 months, and 1 year post randomization]
• European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [Срок оценки: Time Frame: Assessed at baseline, 6 months, and 1 year post randomization.]
• European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck 35 (EORTC QLQ-H&N35) [Срок оценки: Assessed at baseline, 6 months, and 1 year post randomization]
• European Quality of life (Euro-QoL) 5-Dimension 5-Level (EQ-5D-5L): Visual Analog Scale [Срок оценки: Assessed at baseline, 6 months, and 1 year post randomization]
• Neck Dissection Impairment Index (NDII): [Срок оценки: Assessed at baseline, 6 months, and 1 year post randomization]
• Overall Survival [Срок оценки: From the date of randomization until the date of death from any cause, assessed for a minimum of five years.]
• Disease Free Survival [Срок оценки: From the date of randomization until the date of first documented disease recurrence or progression, or death from any cause, whichever occurs first, assessed for a minimum of five years.]
• Regional Recurrence [Срок оценки: From the date of randomization until the date of first documented regional recurrence or until date of death from any cause, assessed throughout the study with a minimum follow-up of five years.]
• Distant Recurrence [Срок оценки: From the date of randomization until the date of first documented distant recurrence or until date of death from any cause, assessed throughout the study with a minimum follow-up of five years.]
• Rate of Salvage Treatment for Primary Emergence [Срок оценки: Assessed throughout the study, with follow-up for at least 5 years from randomization.]
• Rate of Unsalvageable Primary Emergence [Срок оценки: From the date of randomization until the initiation of salvage treatment for primary emergence, assessed throughout the study with a minimum follow-up of five years.]
• Rate of Percutaneous Feeding Tube Insertion and Use [Срок оценки: From the date of randomization through one year, with follow-up assessments at one year. Percutaneous feeding tube insertion and use will be recorded throughout this period.]