A Study of SBRT for Squamous Cell Carcinoma of the Head and Neck (SHINE)

To evaluate the tumour response rate of squamous cell carcinoma of the head and neck following stereotactic body radiotherapy (SBRT) of 45Gy in 5 fractions delivered once every 3-4 days, such that treatment is completed within 15 days.

Cancers of the head and neck region account for approximately 4% of all new cancer cases. Primary skin cancers are the most common malignancy diagnosed in North America with the majority of tumours arising in the cervico-facial region.Together, these tumours comprise a high burden of illness and are often characterized by locally advanced, non-metastatic disease. Determining the optimal treatment for individual patients with advanced cervico-facial cancers of the skin or primary head and neck squamous cell carcinoma (HNSCC) is clinically challenging; standard treatments include combinations of surgery, radiation and chemotherapy, all of which are associated with high rates of acute toxicity and complications. A meta-analysis of randomized controlled trials did not demonstrate benefit with concurrent chemotherapy in patients over the age of 70 or with performance status ≥ 2, and it is recognized that the high burden of medical co-morbidities in HNSCC is associated with poorer prognosis. Some patients without distant metastases may be deemed to have 'incurable' disease due to very advanced tumours, recurrence, severe medical co-morbidities or frailty that prohibit the use of standard surgery, general anaesthetic and/or radiotherapy over 6-7 weeks. When conventional surgery and/or radiotherapy are not recommended by the multi-disciplinary team then patients may be treated with shorter, hypo-fractionated radiotherapy with the goal of symptom relief and local control but at the cost of a lower biological dose. Investigators at the Juravinski Cancer Centre published retrospective results from the '0-7-21' regimen using 24 Gy / 3 fractions which was well tolerated and provided temporary symptom relief in 82% of patients but reported 6 month progression free survival of 39% within the irradiated field; a phase 2 study of previously untreated HNSCC patients deemed to have incurable disease used up to 42 Gy/12 fractions and demonstrated similar rates of initial response and symptom relief but a short progression free survival duration of 3.1 months. One study reported an institutional experience of palliative radiotherapy in newly diagnosed head and neck cancer patients who were deemed to have incurable disease and received a wide range of dose/fractionation regimens. The median radiation dose was 50 Gy and between 57-82% of patients were reported to have any radiological, clinical or symptomatic response to treatment. In these three studies, the patients were older with median ages of 71, 73, and 77 years - and median survival was short 5.2, 5.7 and 6.2 months. With respect to squamous cell carcinoma (SCC) of the skin, there is limited evidence to guide treatment in patients with unresectable or medically inoperable disease, particularly in the head and neck region. There is a need for prospective data on non-surgical treatment options for frail older adults which improve efficacy while limiting the treatment burden. SBRT can limit the number of treatments while delivering a higher, potentially curative dose. An international consortium of 15 high volume cancer centres reported on a survey of practices using SBRT for head and neck cancers. There was heterogeneity in the indications, techniques and doses reported by various institutions. The most common indication was in the setting of recurrent disease and reported doses were in the range of 35-50 Gy in 3-5 fractions. Several institutions reported 1-2 year local control rates of 65-90% with SBRT and acceptable levels of toxicity. To our knowledge, there are no prospective clinical studies evaluating tumour response, toxicity and quality of life in previously unirradiated patients. The goal of the current study is to prospectively evaluate tumour response, toxicity and patient quality of life in patients with HNSCC undergoing SBRT.

Head and Neck Cancer, Squamous Cell Cancer, Squamous Skin Cancer, Stereotactic Body Radiotherapy, SBRT, Radiation Therapy

Eligible and consenting patients will be treated with the dose prescribed in the study of 45Gy in 5 fractions, delivered once every 3-4 days, such that treatment is completed within 15 days (Exceptions: treatment duration of up to 18 days will be allowed to account for cancer centre closures and unforeseen patient issues). Using the Simon optimal two-stage design, 11 patients will be recruited in the first stage. If 6 or less patients have a response, the study will be stopped at the end of stage I, however, if 7 or more patients have a response the study will continue to stage II, in which an additional 27 patients (for a total of 38) will be recruited. At the end of stage II, if 26 or less patients have a response, then H0 will be accepted and the treatment regimen deemed not worthy of further study, however, if 27 or more patients have a response, the treatment regimen will be recommended for further study in phase III.

The dose prescribed in the study will be 45Gy in 5 fractions, delivered once every 3-4 days, such that treatment is completed within 15 days. (e.g. treatment given on Monday/Thursday/Mon/Thurs/Mon) (Exceptions: treatment duration of up to 18 days will be allowed to account for cancer centre closures and unforeseen patient issues.)

Tumour response rate defined as complete or partial response according to Tumour response rate will be defined by RECIST 1.1 criteria

The best overall response across all time points during the study period - up to 24 months after completion of SBRT.

Acute toxicity (during and up to 3 months from the end of treatment) and late toxicity (after 3 months) adverse effects secondary to SBRT treatment will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0) scale.

Determination of local recurrence will be based on based on RECIST criteria 1.1 (see section 11.3 below) and assessed on MRI or CT scan imaging at 12 weeks and any additional imaging/clinical assessments performed during the study.

The FACT-HN Quesionnaire will be administered at Baseline, once during treatment, 6 weeks, 3, 6, 12 months post SBRT treatment. Higher scores represent better qualtiy of life.

Inclusion Criteria: Age >= 60 years Histologically confirmed diagnosis of squamous cell carcinoma of the head and neck region including primary skin SCC; (malignant cells with suspicious/likely SCC will be considered for study if repeat biopsy is not feasible) Clinical stage ≥ T2, or any T-stage with N1-N3 disease, M0 or Mx Measurable tumour present in the head and neck region on clinical examination and/or imaging at time of study enrollment All patients will be assessed by a multi-disciplinary, head and neck oncology team with no systemic therapy being recommended at the time of enrollment Primary surgery not recommended/performed due to any of the following: Unresectable disease and/or borderline resectable Medically inoperable / deemed high risk for post-operative morbidity/mortality by surgical team Patient declined surgery Deemed not to be a candidate for standard fractionation radiotherapy due to poor performance status and/or medical co-morbidities and/or advanced stage disease Eastern Co-operative Oncology Group (ECOG) Performance Status ≤ 3 Exclusion Criteria: Life expectancy ≤ 3 months Chemotherapy or other systemic cancer therapy within 3 months prior to HN SBRT Basal cell carcinoma, Merkel cell, malignant melanoma, adenocarcinoma are excluded HN surgery within 6 months prior to HN SBRT (excision under local anaesthesia is acceptable) Prior radiation treatment to the head and neck region (prior radiotherapy to the skin for non-melanoma skin cancer and deemed to have no risk of overlap with the current field are eligible) Synchronous or recent cancer diagnosis not including the index cancer (other cancers treated curatively with no evidence of disease for >=3 years, or other non- melanoma skin cancers treated with no evidence of disease for >= 6 months are eligible) Confirmed or known distant metastatic disease. Serious non-malignant disease that precludes definitive radiation treatment (e.g. severe cases of scleroderma, systemic lupus erythematosus, rheumatoid arthritis) Unable to provide written, informed consent or complete QoL questionnaires and assessments required on the study Unable to lie flat for 60 minutes in order to have radiation planning and treatment Unable to attend radiation planning and therapy, as well as follow-up care and assessments Unable to provide written, informed consent

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