Trial Information

A Phase I/II Feasibility/Efficacy Study Using Intensity-Modulated Radiation Therapy in Head and Neck (H&N) Cancer Patients to Permit Sparing of Parotid Gland Function

Radiotherapy is the primary treatment modality or an important adjunct treatment for many
patients with H&N carcinoma. Local control is directly related to dose and to the technical
accuracy with which the dose is delivered to the target volume. Traditional radiotherapy
techniques result in significant doses being delivered to normal tissues adjacent to the
target, including the spinal cord and salivary glands. This leaves the patient with
significant acute and late normal tissue toxicity that impacts on both ability to tolerate
the actual treatment and on the patient's long-term quality of life. Recently, we have used
static conformal multisegmental intensity modulated radiotherapy (IMRT) for comprehensive
irradiation of head and neck cancer with dose sparing of uninvolved tissues. This has
resulted in substantial preservation of major salivary gland function in many patients with
primary sites in the oral pharynx, oral cavity, nasopharynx, and pyriform sinus. While our
results to date have shown promising preservation of salivary flow, we do not know whether
patients treated with IMRT have similar local control rates as those treated with standard
radiotherapy. Some investigators have raised concern that by giving a low radiation dose to
areas adjacent to the target volume there is a risk of undertreating disease. On the other
hand, the IMRT delivered with this protocol (called "simultaneous integrated boost", or SIB)
may improve local control rates by delivering the same biologically effective dose in a
shorter overall time period (see below). This is a phase I/II trial which seeks to establish
the efficacy of IMRT for H&N cancer treatment, and further investigate the relationship
between radiation dose to the parotid glands, salivary flow, and quality of life. The
specific objectives of the trial are as follows:

- To assess the local control rate and survival of patients treated with
intensity-modulated radiotherapy using the simultaneous integrated boost (SIB) for
regions at high risk of recurrence;

- To determine the patterns of failure of patients treated with IMRT+SIB;

- To assess the incidence of chronic grade 2 xerostomia after parotid-sparing IMRT using
the RTOG grading scale;

- To assess quality of life of patients during and after IMRT using subjective xerostomia
questionnaire and the University of Washington Quality of Life Head and Neck Symptom
Questionnaire;

- To assess quantitative changes in salivary function before and after IMRT using
sialometry (unstimulated and stimulated whole salivary flow rates).

Patients with squamous cell carcinoma of the H&N will be eligible provided they are over 18
years' age, AJCC stage I-IV with M0 and N0-2 disease, and KPS >=70%. Ineligibility criteria
include previous cancer or H&N radiotherapy, salivary gland dysfunction, or unwilling to
provide informed consent.

Methodology: All patients accrued to this study will have a series of pre-treatment
evaluations, including history, physical, KPS evaluation, CT/MRI of the head and neck, chest
x-ray or CT, dental examination, QOL assessment using the University of Washington QOL H&N
symptom questionnaire (Hassan et al, 1993), and pre-treatment salivary flow measurements.
All salivary flow measurements collected for this study will include unstimulated (resting)
and stimulated (using citric acid solution), with a 5-minute collection time for each.
Accrued patients will belong to one of two cohorts, which will determine the radiotherapy
target volumes and dose levels: Group 1 - Patients who are treated with definitive
radiotherapy (or chemoradiotherapy). The high dose region (PTV66) will consist of all areas
of gross disease plus appropriate planning margin. The lower dose region (PTV54) will
include PTV66 and all at-risk draining lymphatics of the neck. Group 2 - Patients treated
with surgery and post-operative radiotherapy. The high-dose region (PTV60) will consist of
the areas of previous gross disease and regions of the neck with metastatic lymph node
involvement. The low-dose region (PTV54) will include PTV60 plus the remainder of the
surgical bed and any additional regional lymphatic tissue considered to be at risk of
harboring occult disease. All patients will be treated in 30 treatments (1 treatment per
day, 5 days per week, for 6 weeks). PTV66 will receive 66 Gy, PTV54 will receive 54 Gy, etc.
Thus different target regions will receive different doses per day (ranging from 1.8 to
2.2). In theory, giving high-risk regions a higher dose per day (hypofractionation) allows
tumour cells less time to repopulate and should improve control rates (Fowler, 2000).

Investigations during and after treatment: Patients will have weekly toxicity assessments
during radiotherapy. Follow-up after completion of RT will include history/physical, QOL
assessment, and salivary flow collections. These assessments will be done at 4, 8, and 12
weeks, then every 1.5 months until 1 year. Follow-up beyond 1 year is at the physician's
discretion but normally will involve visits every 3-4 months.

Statistical considerations: The sample size for this trial is based on the expected local
control rate of similar patients treated with standard radiotherapy. For group 1 (patients
treated with definitive radiotherapy) this is difficult to predict a priori because of the
expected heterogeneity of stages and primary sites of accrued patients. However, stage I-II
patients treated with RT alone, and selected stage III patients treated with
chemoradiotherapy have 2-year local control rates of 70-80%. For group 2 (patients treated
with surgery with high-risk features necessitating post-op RT), the expected local control
rate is also approximately 70%. Assuming a power of 70%, significance of 5%, and a
historical rate of local control of 75% (combined), the required number of patients to
detect a 10% change in local control is 120.7. We will therefore accrue 120 patients, at an
anticipated rate of 2-3 patients per month for 2-4 years.