Clinical trial NCT06578871: Surgery and Reducing Ionizing Radiation of the Unknown Primary
Official title: Surgery for the Unknown Primary in the Era of p16-positive Oropharyngeal Squamous Cell Carcinoma: Reducing Ionizing Radiation (SUPERIOR): A Randomized Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
HPV Positive Oropharyngeal Squamous Cell Carcinoma
Keywords: HPV-Mediated PUK
Head and Neck Cancer
P16+
Radiation Therapy
Oropharyngeal Cancer
Squamous Cell Carcinoma
Transoral Robotic Surgery (TORS)
Mucosal Radiation
SUPERIOR Trial
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
Collaborators: name: Dr. Jake Jervis-Bardy
name: Dr. David Palma
name: Dr. Adam Mutsaers
First posted: 2024-08-29
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomized phase II study. Patients will be randomized between current standard of care treatment (Arm 1) vs. omission of radiation mucosal surfaces (Arm 2) in a 1:2 ratio.
Primary purpose: TREATMENT

Brief summary: About 3% of people with head and neck cancer have cancer in their lymph nodes, but doctors are unable to find the primary tumour. This situation has become more common due to human papillomavirus (HPV), a virus linked to certain cancers. Generally, patients with HPV-related cancers have a good outlook, with around 90% surviving for at least five years.

Recent advancements in medical technology, such as advanced imaging and specialized surgeries, have significantly improved doctors' ability to find these hidden tumours. These techniques can locate the primary tumour in 70-80% of cases. If the tumour remains undetected, it could be very small or potentially eliminated by the body's immune system.

The best way to treat this type of cancer is still debated. Current treatment options include surgery to remove lymph nodes or radiation therapy. There is no clear agreement on which areas should receive radiation. Often, surgery is performed on one side of the throat to try and locate the tumour's origin.

Researchers are exploring ways to minimize the harmful side effects of treatment. Some studies suggest that surgery alone might be sufficient for patients with small tumours in their neck, but more research is needed. Another important question is whether radiation needs to cover the entire throat area. Recent findings suggest that omitting radiation from some areas might reduce side effects such as difficulty swallowing and dry mouth.

The SUPERIOR trial aims to investigate whether reducing the amount of radiation can still be effective and improve patients' quality of life. The study also examines whether surgery alone is adequate for certain patients with HPV-related cancers.

Detailed description: 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.

Eligibility criteria: Inclusion criteria for the Registration phase

* p16 positive PUK SCC of the neck
* Age 18 years or older
* Willing to provide informed consent
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Clinical nodal stage N1, AJCC 8th edition (i.e. clinical unilateral nodal disease, none larger than 6 cm)
* Complete clinical work-up, including CT neck, physical examination with nasopharyngoscopy, and PET/CT, with no evidence of a primary tumor. The PET/CT scan must be without focal metabolic activity concerning for a primary tumor, in the opinion of the nuclear medicine physician. Metabolic activity, particularly in the tonsils and base of the tongue which is within normal physiologic range, does not exclude participation.

Inclusion criteria for the Randomization phase

* Completed ipsilateral tonsillectomy and base of tongue mucosectomy with no evidence of a primary tumor

  o Note, patients who had a PET/CT that was initially positive, and therefore not meeting criteria in 4.10, but panendoscopy with biopsies of the fluorodeoxyglucose (FDG)-avid areas do not show malignancy, can then be enrolled and would be returned the OR for a neck dissection prior to randomization
* Ipsilateral nodal disease on pathology with no evidence of extranodal extension

Exclusion Criteria:

* Radiological or pathological extra-nodal extension
* Epstein-Barr Virus (EBV)-positive
* Clinical nodal stage (i.e. before neck dissection) N2-3, AJCC 8th edition (ie. bilateral nodes or node \>6cm)
* Pathological nodal stage (i.e. after neck dissection) pN3
* Prior history of head and neck cancer within 2 years
* Any other active invasive malignancy, except non-melanotic skin cancers, low-risk prostate cancer, and stage I-IVA papillary or follicular thyroid cancer
* Known metastatic disease
* Unable to complete QOL questionnaires
* Pregnant or lactating women

Primary outcomes:
measure: Primary Endpoint: Rate of Primary Emergence of Mucosal p16-Positive Squamous Cell Carcinoma
timeFrame: 2 years
Secondary outcomes:
measure: MD Anderson Dysphagia Inventory (MDADI)
timeFrame: Assessed at baseline, 6 months, and 1 year post randomization
measure: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
timeFrame: Time Frame: Assessed at baseline, 6 months, and 1 year post randomization.
measure: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck 35 (EORTC QLQ-H&N35)
timeFrame: Assessed at baseline, 6 months, and 1 year post randomization
measure: European Quality of life (Euro-QoL) 5-Dimension 5-Level (EQ-5D-5L): Visual Analog Scale
timeFrame: Assessed at baseline, 6 months, and 1 year post randomization
measure: Neck Dissection Impairment Index (NDII):
timeFrame: Assessed at baseline, 6 months, and 1 year post randomization
measure: Overall Survival
timeFrame: From the date of randomization until the date of death from any cause, assessed for a minimum of five years.
measure: Disease Free Survival
timeFrame: 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.
measure: Regional Recurrence
timeFrame: 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.
measure: Distant Recurrence
timeFrame: 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.
measure: Rate of Salvage Treatment for Primary Emergence
timeFrame: Assessed throughout the study, with follow-up for at least 5 years from randomization.
measure: Rate of Unsalvageable Primary Emergence
timeFrame: 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.
measure: Rate of Percutaneous Feeding Tube Insertion and Use
timeFrame: 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.
measure: Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) score
timeFrame: From the date of randomization, with swallowing function assessed at one year post-randomization.
measure: Functional Oral Intake Score (FOIS)
timeFrame: From the date of randomization, with swallowing function assessed at one year post-randomization.
measure: Toxicity : Assessment of Treatment-Related Adverse Events Using CTCAE v5.0
timeFrame: Toxicity will be monitored throughout the study, with evaluations at regular intervals up to 1 year or until date of death, whichever comes first, post-randomization.
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Adelaide
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
Study officials:
affiliation: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
name: Adrian I Mendez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Adelaide Hospital
name: Jake Jervis-Bardy, MD
role: PRINCIPAL_INVESTIGATOR
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