Neoplasms

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Carcinoma, Squamous Cell

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Xerostomia

Laryngeal Diseases

Salivary Gland Diseases

Mouth Diseases

Stomatognathic Diseases

Laryngeal Cancer

Hypopharyngeal Cancer

Metastatic Squamous Neck Cancer With Occult Primary

Submandibular salivary gland transfer at the time of surgery for the primary tumor and neck nodes followed by post-operative radiation therapy.

Seikaly and Jha method of submandibular salivary gland transfer at the time of surgery for the primary tumor and neck nodes on Day 1

salivary gland transfer

Dose ranging from 54-70 Gy over 5.5-7 weeks, at 2.0 Gy/fraction. Starts within 4-6 weeks of surgery.

Post-operative radiation therapy

Naresh Jha, MBBS

RATIONALE: Moving a salivary gland out of the area that will undergo radiation therapy may protect the gland from side effects of radiation therapy and may prevent xerostomia (dry mouth).

PURPOSE: Phase II trial to study the effectiveness of salivary gland surgery in preventing xerostomia in patients who are undergoing radiation therapy for head and neck cancer.

OBJECTIVES:

* Determine the reproducibility of the surgical technique of submandibular salivary gland transfer in patients with head and neck cancer.
* Determine the rate and severity of radiation-induced xerostomia after this surgery in these patients.
* Determine the pattern of recurrence, disease-free survival, and overall survival of patients treated with this surgery followed by radiotherapy.
* Determine the quality of life of patients treated with this regimen.

OUTLINE: This is a multicenter study.

Patients undergo surgical transfer of the submandibular salivary gland to the submental space.

Within 4-6 weeks after surgery, patients undergo radiotherapy once daily, 5 days a week for 5 ½ to 7 weeks in the absence of disease progression or unacceptable toxicity.

Salivary scans are performed before surgery, at 2-3 weeks after surgery, and then at 6 months from the start of radiotherapy.

Quality of life is assessed at baseline and at 3, 6, and 12 months from the start of radiotherapy.

Patients are followed every 3 months for 2 years and then every 6 months for 3 years and then annually.

PROJECTED ACCRUAL: A total of 11-48 patients will be accrued for this study within 1.6 years.

Salivary Gland Surgery Before Radiation Therapy in Preventing Radiation-Caused Xerostomia in Patients With Head and Neck Cancer

A Phase II Study Of Submandibular Salivary Gland Transfer To The Submental Space Prior To Start Of Radiation Treatment For Prevention Of Radiation-Induced Xerostomia In Head And Neck Cancer Patients

Surgery will be scored as "per protocol prescription" if scored as such by both central reviewers- the Study Chair and the Radiation Therapy Oncology Group Head and Neck Committee Surgical Chair. If 21 or more of 43 subjects are scored as having surgery "per protocol prescription", then the technique will be considered reproducible with 80% power and 5% type I error using Simon's two stage design with unacceptable/acceptable rates set at 60%/80%.

The proportion of patients who experience grade 2 or higher xerostomia or start amifostine and/or pilocarpine within 90 days of the start of radiation therapy. A proportion less than or equal to 51% would be considered acceptable based on the results of the U.S. Bioscience phase III amifostine trial (this trial preceded FDAAA requirements).

Salivary gland functioning classified as "Non-functioning", "Minimal function", "Well-functioning but some impairment", "Normal functioning", or "Other" is determined by central review of scintigraphy scans using sodium pertechnetate (Na-99mTcO4-) with a sialagogue (lemon juice) administered halfway through the study to determine if secretory function is maintained.

The University of Washington Head and Neck Symptom Questionnaire, also referred to as the University of Washington Health Related Quality of Life tool (UW-QOL) was modified for use by the Radiation Therapy Oncology Group (RTOG). The resulting UW-QOL-RTOG modification is a valid tool that can be used to assess symptom burden of head and neck cancer patients receiving radiation therapy or those who have recently completed radiation. The UW-QOL-RTOG modification consists of 15 items with response options ranging from 10-50, in multiples of 10. That is, the lowest symptom burden is rated as 10, while the highest symptom burden is rated as 50. The individual item scores are averaged to obtain the final score which also ranges from 10 to 50. This scoring results in a lower score indicating greater HR-QOL; and conversely, higher scores indicating lower health-related quality of life (HR-QOL). Change = baseline score - one year score, such that a positive change score indicates improvement.

Facial edema was noted as present or absent following surgery.

Adverse events are graded using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) v2.0. Grade refers to the severity of the toxicity by assigning Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to toxicity. "Acute" refers to toxicities occurring less than or equal to 90 days from the start of radiation therapy.

Adverse events are graded using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) v2.0. Grade refers to the severity of the toxicity by assigning Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to toxicity. "Late" refers to toxicities occurring at least 91 days from the start of radiation therapy.

Failure was defined as local, regional, or distant recurrence/progression, second primary tumor, or death due to any cause. Disease-free survival time is defined as time from registration to the the date of failure or last known follow-up (censored). Disease-free survival rate is estimated using the kaplan-meier method.

Failure was defined as death due to any cause. Survival time is defined as time from registration to the the date of failure or last known follow-up (censored). Survival rate is estimated using the kaplan-meier method.

National Cancer Institute (NCI)

Radiation Therapy Oncology Group

Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE). Please note that different numbers of patients were at risk for different treatment-specific adverse events due to the timing and sequence of treatments.

Surgery + Transfer + Radiation

Age, Continuous

Sex: Female, Male

All eligible patients who started study treatment.

Wendy Seiferheld

Eligible patients who started study treatment.

Number of Patients Scored as Having the Surgical Technique of Submandibular Salivary Gland Transfer Performed "Per Protocol"

Percentage of Patients With Acute Xerostomia

Pre-surgery

Post-surgery

Post-radiotherapy

Eligible patients with salivary scans submitted

Percentage of Patients With Normal Functioning Transferred Submandibular Gland

Eligible patients with both baseline and 1-year questionnaire completed

Change From Baseline to One Year in Total Score on the Modified University of Washington Head and Neck Symptom Questionnaire

Eligible patients who received the procedure

Percentage of Patients Experiencing Facial Edema Following Surgery

Percentage of Patients Experiencing Acute Grade 3-4 Toxicity Definitely, Probably, or Possibly Related to Radiation Therapy or Chemotherapy

Eligible patients who started RT and had toxicity data at least 90 days from the end of RT

Percentage of Patients Experiencing Late Grade 3-4 Toxicity Definitely, Probably, or Possibly Related to Radiation Therapy

Eligible patients who started study treatment

Disease-free Survival Rate at 2 Years

Overall Survival Rate at 2 Years

Overall Study

Salivary gland transfer

Helical Tomotherapy treatment

Rufus Scrimger, MD, FRCPC

A study for head and neck cancer patients to evaluate the feasibility of combining salivary gland transfer surgical procedure and IMRT helical tomotherapy to reduce dryness of mouth.

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.

A Pilot Study to Evaluate the Feasibility of Combining Submandibular Salivary Gland Tx & IMRT Tomo to Reduce Xerostomia

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

combining submandibular salivary gland transfer procedure and intensity modulated radiation therapy (helical tomotherapy) to reduce dryness of mouth in head and neck cancer patients after surgery

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Salivary Gland Surgery Before Radiation Therapy in Preventing Radiation-Caused Xerostomia in Patients With Head and Neck Cancer	NCT00068237	Head and Neck C... Radiation Toxic... Xerostomia	salivary gland ... Post-operative ...	18 Years -	Radiation Therapy Oncology Group
A Pilot Study to Evaluate the Feasibility of Combining Submandibular Salivary Gland Tx & IMRT Tomo to Reduce Xerostomia	NCT00497406	Head and Neck C...	Salivary gland ... Helical Tomothe...	18 Years -	AHS Cancer Control Alberta

Spots Global Cancer Trial Database for salivary gland transfer