Trial Information

A Pilot Study to Evaluate the Feasibility of Combining Submandibular Salivary Gland Transfer Procedure and Intensity Modulated Radiation Therapy (Helical Tomotherapy) to Reduce Dryness of Mouth (Xerostomia) in Head and Neck Cancer Patients After Surgery

Background Information Radiation therapy is used in a definitive manner or as an adjunct to
surgery in most of the head and neck cancer patients which inevitably lead to xerostomia
(salivary gland dysfunction) in almost all patients. Xerostomia is debilitating condition
which adversely affects the deglutition, mastication, gustation, speech and lead to
increased susceptibility of structures in mouth to infection. Xerostomia may also interfere
with nutrition and sleep of patient and thereby has a significant negative impact on
patient's quality of life. Various modalities have been explored to prevent or decrease the
incidence of xerostomia and the most successful methods are; use of Intensity modulated
radiotherapy (IMRT) to spare the parotid salivary gland from radiation, Sparing
submandibular salivary gland from radiation by it's transfer to sub mental space, use of
Amifostine to protect salivary glands from radiation and use of cholinergic agonists like
pilocarpine to stimulate salivary secretion. Both amifostine and pilocarpine are associated
with significant side effects and amifostine is too costly to be used in routine practice.
At our center, we were successful in decreasing the incidence of xerostomia significantly by
using either IMRT sparing parotid gland (Parliament et al 2004) or submandibular gland
transfer (SGT) sparing submandibular gland (Jha et al 2003)without compromising the tumor
control rates. Both these modalities were not associated with any added toxicity which makes
these methods superior to pilocarpine and amifostine. To improve upon our results by sparing
both the major salivary glands, we plan to explore a combined approach of IMRT and SGT in
head and neck cancer patients after surgery. For IMRT we had used "step-and-shoot" technique
on a Varian 2300 EX linac with 120-leaf Millenium MLC. Since December 2002, the Cross Cancer
Institute has had a helical tomotherapy unit at its disposal for IMRT and a planning study
(van Vulpen et al 2005) conducted comparing the step-and-shoot IMRT and Helical tomotherapy
for 5 oropharynx patients showed that tomotherapy plans compared favorably with step-
and-shoot plans regarding sparing of the parotid glands. Hence we intend to use helical
tomotherapy as an IMRT tool for this study.

Objectives - primary and secondary Primary objective is to assess the feasibility of sparing
parotid and transferred submandibular gland by combining IMRT using helical tomotherapy with
SGT in cancers of oropharynx, larynx, hypopharynx after primary surgery and patients with
unknown primary cancer with neck nodes after neck dissection.

Secondary objectives are to assess the incidence of xerostomia subjectively by xerostomia
specific &University of Washington Quality of Life Head and Neck Symptom questionnaire and
objectively by sialometry and salivary scintigraphy after parotid-sparing IMRT+ SGT. We also
intend to evaluate the speech and swallowing function of patients before and after
radiation. All these functional outcomes will be correlated with the dose-volume histograms
of salivary glands.

Study Design Primary squamous cell carcinomas of oropharynx, larynx, hypopharynx Unknown
primary with neck nodes with squamous cell carcinoma histology

? Radical surgery for primary cancers of oropharynx, larynx, hypo pharynx or Neck
dissection for unknown primary with neck nodes

+ Selective neck dissection(level I-III) and SGT on opposite side for lateralized primary
and on the side of N0 neck for midline primary

?

IMRT with Helical tomotherapy sparing the parotid glands and transferred submandibular gland
+ chemotherapy

Statistical Analysis - Power and/or Sample Size Relation This pilot study on 12 patients
will be considered as feasible if we can limit the mean radiation dose to one parotid and
one transferred submandibular gland to less than 26Gy while giving a radiation dose of 60Gy
to PTV 1 and 54 Gy to PTV 2 .We intend to report only the descriptive statistics related to
incidence and severity of xerostomia.

Stopping Rules Radiation treatment will be withheld if any patient develops acute toxicity
of RTOG grade?4 or any unpredictable adverse events. Other than this, the decision to
stop/delay treatment if clinically indicated will be at the discretion of the treating
physician.

Data Safety Monitoring Committee Data will be handled by Juliette Jordan as per rules of
Alberta Cancer Board. Recruitment & Eligibility Criteria " Twelve patients with
histologically proven newly diagnosed squamous cell carcinoma of the oropharynx, larynx,
hypo pharynx and unknown primary cancer with neck nodes after primary surgery will be
recruited to this study.

" AJCC stage I-IV patients are eligible provided they are M0 and N0-2b. " age 18, and
Karnofsky performance status 70 " patients must sign a study-specific informed consent
form " Patients with: N3/N2C/ M1 disease, salivary gland diseases like Sjogren's syndrome,
prior or concurrent malignancy, prior or concurrent malignancy, pre-epiglottic space
involvement on pathological examination, involvement of level I nodes on either side of
neck, post op recurrent disease at presentation will not be eligible for this study.

Additional procedures and investigations that will be done in this study are outlined below.

Submandibular Gland Transfer We are using the retrograde flow method for gland transfer.
Retrograde flow flaps are well established techniques that are extensively used in finger
and hand reconstructions. The gland is dissected and left pedicled on the artery, vein, and
submandibular region. The great auricular nerve is dissected, harvested and preserved for
later use. The facial artery and vein are cut just proximal to their branches supplying the
gland. The efferent nerves of the submandibular ganglion are also cut. The gland is then
repositioned in the submental space after the mylohyoid muscle is cut to allow the
repositioning of the submandibular duct. The efferent nerves of the submandibular region are
then reattached to the gland with the greater auricular nerve interposition graft. In our
experience (more than 200 patients so far) we have experienced only one case of recurrence
of tumor in the grafted area.

Sialometry Whole salivary flow rates, unstimulated and stimulated, will be measured from the
floor of the mouth and labial vestibule preoperatively and at 2-3 weeks after surgery before
start of radiation treatment. After radiation treatment, flow evaluation will be done at 6
months and 12 months. Each time, the flow rate will be measured at rest and after
stimulation. Stimulated flow rates will be measured by dropping 0.2 ml of 6% citric acid
solution on the dorsal surface of the tongue every 30 seconds (Dawes 1975).Salivary samples
will be collected by means of a an appliance (Pederson et al 1985) consisting of a Drummond
micropipette holder (for use with 20 microlitre micropipettes) fitted with a 2 ml latex
dropper bulb. A 2.5 cm length of 50 microlitre micropipette is inserted into the holder
until its outer end no longer protrudes. During collection, the patient tips the head slight
forward to produce pooling of saliva at the anterior floor of mouth and mandibular labial
vestibule. The micropipette extruding from the end of the collection device is used to
aspirate the pooled salivary secretions from these two sites. As saliva flows up the
micropipette, it spills into the glass sleeve of the collection device between the top of
the silicon end-piece and the top of the micropipette.

Salivary Scintigraphy Salivary gland scintigraphy will be carried out using sodium
pertechnate 99mTc 04,before surgery,2-3 weeks after surgery and 6 months,12 months after
radiation therapy to evaluate the morphology and function of the "transferred gland". This
will be compared with the salivary gland morphology and function that will receive radiation
treatment. After 148 MBq of 99mTc 04 is rapidly injected with computer acquisition of 1 min
frames, for a total of 30 min. After 15 minutes time point, the patient is requested to
suck on the juice of a lemon by a straw, in order to provoke salivary secretion.

Speech and Swallowing Assessments This assessment will be done at the Head and neck Surgery
Functional Assessment Laboratory is housed within COMPRU at the Misericordia Hospital. Each
patient will be scheduled for 4 predetermined assessment visits:1) preoperative; 2) 2-4
weeks postoperative; 3) 6-months post-radiation therapy; and 4) 1-year post radiation
therapy. At each of these sessions, speech, mastication, deglutition, and quality of life
will be assessed. Speech function will be assessed by recording the voice of patient using
audiotapes. Masticatory efficiency will be assessed using an electrognathograph (BioPak,
Version 2.0, Milwaukee, WI), a clinical tool that measures mandibular movement using a
sensory array to track the position of a magnet placed on a patient's mandibular incisors.
After placement of both the magnet on the mandibular dentition and the sensory array on the
head, each patient will be asked to chew a wine gum and ¼ of a digestive cookie. Various
aspects of mastication will be assessed including the number of chewing strokes and time
passing before the first swallow of both the candy and the cookie. Swallowing function will
be assessed by fluoroscopic visualization while the patient is swallowing food substances of
different consistencies coated with Barium.