Surgery for the Unknown Primary in the Era of p16-positive Oropharyngeal Squamous Cell Carcinoma: Reducing Ionizing Radiation (SUPERIOR): A Randomized Trial
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 90
- 试验地点
- 3
- 主要终点
- Primary Endpoint: Rate of Primary Emergence of Mucosal p16-Positive Squamous Cell Carcinoma
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
The SUPERIOR trial employs a 1:2 randomization ratio using a permuted block design with block sizes known only to the statistician. Stratification factors include smoking status (>10 pack-years vs. ≤10 pack-years) and pathologic nodal burden (1 node positive vs. >1 node positive). Although participants and treating clinicians are aware of the treatment allocations, outcome assessors and data analysts are blinded to the treatment arms to ensure unbiased assessment and analysis of trial results.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Arm1: Standard of Care Treatment
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
干预措施: Intensity Modulated Radiotherapy (IMRT) to Mucosa at Risk (Radiation)
Arm1: Standard of Care Treatment
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
干预措施: Surgical Intervention (Procedure)
Arm1: Standard of Care Treatment
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
干预措施: Intensity Modulated Radiotherapy (IMRT) to Ipsilateral Neck (Radiation)
Arm 2: Omission of IMRT to Risk Mucosa but conditional IMRT to Neck
- If N1 with single node <= 3cm, no further treatment
- If multiple ipsilateral nodes or single ipsilateral node >3 cm, radiation to Neck only
干预措施: Surgical Intervention (Procedure)
Arm 2: Omission of IMRT to Risk Mucosa but conditional IMRT to Neck
- If N1 with single node <= 3cm, no further treatment
- If multiple ipsilateral nodes or single ipsilateral node >3 cm, radiation to Neck only
干预措施: Intensity Modulated Radiotherapy (IMRT) to Ipsilateral Neck (Radiation)
结局指标
主要结局
Primary Endpoint: Rate of Primary Emergence of Mucosal p16-Positive Squamous Cell Carcinoma
时间窗: 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.
次要结局
- MD Anderson Dysphagia Inventory (MDADI)(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(Assessed at baseline, 6 months, and 1 year post randomization)
- Functional Oral Intake Score (FOIS)(From the date of randomization, with swallowing function assessed at one year post-randomization.)
- 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.)
- Rate of Salvage Treatment for Primary Emergence(Assessed throughout the study, with follow-up for at least 5 years from randomization.)
- 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.)
- Neck Dissection Impairment Index (NDII):(Assessed at baseline, 6 months, and 1 year post randomization)
- 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.)
- Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) score(From the date of randomization, with swallowing function assessed at one year post-randomization.)
- 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.)
- 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)
- Overall Survival(From the date of randomization until the date of death from any cause, assessed for a minimum of five years.)
- 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.)
- 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.)
- 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.)
研究者
Adrian Mendez
Study Principal Investigator
London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's