Surgery and Reducing Ionizing Radiation of the Unknown Primary
- Conditions
- HPV Positive Oropharyngeal Squamous Cell CarcinomaHead and Neck Squamous Cell Carcinoma
- Interventions
- Procedure: Surgical InterventionRadiation: Intensity Modulated Radiotherapy (IMRT) to Mucosa at RiskRadiation: Intensity Modulated Radiotherapy (IMRT) to Ipsilateral Neck
- Registration Number
- NCT06578871
- Lead Sponsor
- Adrian Mendez
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 90
Not provided
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 2: Omission of IMRT to Risk Mucosa but conditional IMRT to Neck Surgical Intervention * If N1 with single node \<= 3cm, no further treatment * If multiple ipsilateral nodes or single ipsilateral node \>3 cm, radiation to Neck only Arm 2: Omission of IMRT to Risk Mucosa but conditional IMRT to Neck Intensity Modulated Radiotherapy (IMRT) to Ipsilateral Neck * If N1 with single node \<= 3cm, no further treatment * If multiple ipsilateral nodes or single ipsilateral node \>3 cm, radiation to Neck only Arm1: Standard of Care Treatment Intensity Modulated Radiotherapy (IMRT) to Mucosa at Risk Radiotherapy to Ipsilateral Neck and to risk Mucosa There are two possible dose levels: * 60 Gy in 30 fractions over 6 weeks (CTV60) o This applies to the dissected levels of the neck * 54 Gy in 30 fractions over 6 weeks (CTV54) * This applies to the mucosal surfaces. Patients randomized to Arm 2 will not have the mucosal surfaces treated Arm1: Standard of Care Treatment Surgical Intervention Radiotherapy to Ipsilateral Neck and to risk Mucosa There are two possible dose levels: * 60 Gy in 30 fractions over 6 weeks (CTV60) o This applies to the dissected levels of the neck * 54 Gy in 30 fractions over 6 weeks (CTV54) * This applies to the mucosal surfaces. Patients randomized to Arm 2 will not have the mucosal surfaces treated Arm1: Standard of Care Treatment Intensity Modulated Radiotherapy (IMRT) to Ipsilateral Neck Radiotherapy to Ipsilateral Neck and to risk Mucosa There are two possible dose levels: * 60 Gy in 30 fractions over 6 weeks (CTV60) o This applies to the dissected levels of the neck * 54 Gy in 30 fractions over 6 weeks (CTV54) * This applies to the mucosal surfaces. Patients randomized to Arm 2 will not have the mucosal surfaces treated
- Primary Outcome Measures
Name Time Method Primary Endpoint: Rate of Primary Emergence of Mucosal p16-Positive Squamous Cell Carcinoma 2 years The primary endpoint of this clinical trial is to assess the rate at which a primary mucosal p16-positive squamous cell carcinoma (SCC) emerges in the upper aerodigestive tract (which includes the oral cavity, pharynx, or larynx) in patients with p16-positive PUK of the head and neck. This rate will be compared to a historical control to determine the impact of omitting mucosal radiation in these patients. The primary objective is to evaluate the oncologic outcomes associated with this treatment approach.
- Secondary Outcome Measures
Name Time Method MD Anderson Dysphagia Inventory (MDADI) Assessed at baseline, 6 months, and 1 year post randomization MD Anderson Dysphagia Inventory (MDADI): Measures the impact of swallowing difficulties on a patient's daily life and emotional well-being.
Scale Range: 20 to 100. Interpretation: Higher scores indicate a better outcome, reflecting better swallowing function and less impact on quality of life.European Quality of life (Euro-QoL) 5-Dimension 5-Level (EQ-5D-5L): Visual Analog Scale Assessed at baseline, 6 months, and 1 year post randomization Outcome Measure: Health-related quality of life across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
Scale Range: -0.281 to 1 (Index value) and 0 to 100 (Visual Analog Scale).
Interpretation: For the Index value, higher scores indicate a better outcome (better health-related quality of life). For the Visual Analog Scale, higher scores indicate better perceived overall health.Functional Oral Intake Score (FOIS) From the date of randomization, with swallowing function assessed at one year post-randomization. Functional Oral Intake Score (FOIS): Assesses the ability to consume food and liquids by mouth. It assesses how much and what type of food and liquids a patient can safely consume.
Scale Used: The FOIS is a categorical scale with grades ranging from 1 to 7.
Lower Scores: Indicate greater dependence on non-oral feeding methods or more restricted oral intake.
Higher Scores: Indicate greater ability to consume a wide variety of foods and liquids by mouth, with fewer restrictions.Toxicity : Assessment of Treatment-Related Adverse Events Using CTCAE v5.0 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. Toxicity will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, which categorizes the severity and type of adverse effects experienced by patients.
The assessment focuses on:
Severity of Adverse Events: Evaluate the intensity of side effects related to treatment, ranging from mild to severe.
Type of Adverse Events: Identifies specific side effects, such as nausea, fatigue, pain, and other treatment-related symptoms.
Frequency and Duration: Monitors how often and for how long patients experience these adverse effects.Rate of Salvage Treatment for Primary Emergence Assessed throughout the study, with follow-up for at least 5 years from randomization. The frequency of additional treatments (surgery ± radiotherapy) required for the emergence of a p16-positive primary mucosal tumour, with the intent of cure.
Distant Recurrence 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. The development of recurrent cancer outside the upper aerodigestive tract and neck levels.
Overall Survival From the date of randomization until the date of death from any cause, assessed for a minimum of five years. Overall Survival (OS): Defined as the time from randomization until death or the last follow-up, whichever occurs first.
Neck Dissection Impairment Index (NDII): Assessed at baseline, 6 months, and 1 year post randomization Outcome Measure: Specific impairments related to neck dissection, including physical and functional issues in the neck area.
Scale Range: 0 to 100.
Interpretation: Higher scores indicate a better outcome, reflecting fewer impairments and better neck function.Regional Recurrence 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. The occurrence of recurrent cancer specifically within the nodal levels of the neck (levels I-VI).
Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) score From the date of randomization, with swallowing function assessed at one year post-randomization. Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) score: Measures the severity of swallowing dysfunction particularly related to the impact of cancer treatment on swallowing ability. It evaluates changes in swallowing function as seen through imaging techniques, such as fluoroscopy or videofluoroscopy.
Scale Used: Typically, the DIGEST score is a categorical scale with grades ranging from 0 to 4.
Lower Scores: Indicate less severe swallowing dysfunction or no dysfunction. Higher Scores: Indicate more severe swallowing dysfunction, with a greater impact on the ability to eat and drink.European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck 35 (EORTC QLQ-H&N35) Assessed at baseline, 6 months, and 1 year post randomization Outcome Measure: Head and neck cancer-specific symptoms and issues, particularly related to treatment effects.
Scale Range: 0 to 100. Interpretation: Higher scores on symptom scales indicate a worse outcome, reflecting more severe symptoms or problems related to head and neck cancer.European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Time Frame: Assessed at baseline, 6 months, and 1 year post randomization. Outcome Measure: General health status and overall quality of life in cancer patients, including physical functioning, role functioning, emotional functioning, and overall health.
Scale Range: 0 to 100.
Interpretation: Higher scores on functional scales and global health status indicate a better outcome. Higher scores on symptom scales indicate a worse outcome.Disease Free Survival 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. The time from randomization until the first occurrence of disease recurrence, death, or the last follow-up, whichever comes first.
Rate of Unsalvageable Primary Emergence 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. The frequency of emergence of a p16-positive primary mucosal tumour that cannot be treated with surgery or radiotherapy with the intent of cure.
Rate of Percutaneous Feeding Tube Insertion and Use 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. The frequency of percutaneous feeding tube insertion and the rate of feeding tube use 1 year after randomization.
Trial Locations
- Locations (3)
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
London Health Sciences Centre
🇨🇦London, Ontario, Canada
Flinders Medical Centre
🇦🇺Adelaide, South Australia, Australia