Clinical Investigation
A Phase II Study of Submandibular Gland Transfer Prior to Radiation for Prevention of Radiation-induced Xerostomia in Head-and-Neck Cancer (RTOG 0244)

Presented in part at the 52nd Annual Meeting of the American Society for Radiation Oncology (ASTRO) in San Diego, CA, on October 31-November 4, 2010.
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Purpose

We report the results of a phase II study to determine the reproducibility of a submandibular salivary gland transfer (SGT) surgical technique for prevention of radiation (XRT)-induced xerostomia in a multi-institutional setting and to assess severity of xerostomia.

Methods and Materials

Eligible patients had surgery for primary, neck dissection, and SGT, followed by XRT, during which the transferred salivary gland was shielded. Intensity modulated radiation therapy, amifostine, and pilocarpine were not allowed, but postoperative chemotherapy was allowed. Each operation was reviewed by 2 reviewers and radiation by 1 reviewer. If 13 or more (of 43) were “not per protocol,” then the technique would be considered not reproducible as per study design. The secondary endpoint was the rate of acute xerostomia, grade 2 or higher, and a rate of ≤51% was acceptable.

Results

Forty-four of the total 49 patients were analyzable: male (81.8%), oropharynx (63.6%), stage IV (61.4%), median age 56.5 years. SGT was “per protocol” or within acceptable variation in 34 patients (77.3%) and XRT in 79.5%. Nine patients (20.9%) developed grade 2 acute xerostomia; 2 had grade 0-1 xerostomia (4.7%) but started on amifostine/pilocarpine. Treatment for these 11 patients (25.6%) was considered a failure for the xerostomia endpoint. Thirteen patients died; median follow-up for 31 surviving patients was 2.9 years. Two-year overall and disease-free survival rates were 76.4% and 71.7%, respectively.

Conclusions

The technique of submandibular SGT is reproducible in a multicenter setting. Seventy-four percent of patients were prevented from XRT-induced acute xerostomia.

Introduction

Over 40,000 cases of head-and-neck cancer are diagnosed every year in the United States. Radiation treatment is a primary or secondary therapeutic modality with most cases, resulting in xerostomia and adversely affecting patients’ quality of life (1). Xerostomia impairs mastication, deglutition, and gustation, as well as causes nutritional compromise, sleep disruptions, and changes in oral microbial flora leading to caries (1). Several strategies such as amifostine therapy (2), intensity modulated radiation therapy (IMRT) 3, 4, pilocarpine therapy 5, 6, and acupuncture have been tried in an attempt to reduce xerostomia.

A new surgical procedure for the prevention of xerostomia through submandibular gland transfer (SGT) to the submental space was recently described. The transferred gland is then shielded during radiation treatment 7, 8, 9. Jha et al (7) and Seikaly et al 8, 9 conducted prospective, phase II studies for the management of xerostomia by surgical transfer of submandibular salivary gland to the submental space prior to starting radiation therapy (XRT). Surgery was the prime mode of management, followed by XRT. Eighty-one percent of patients had no or minimal xerostomia, and 19% had moderate to severe xerostomia. Long-term results were also published showing preservation of saliva in 83% of patients 2 years after XRT. These results have been confirmed by other investigators 10, 11.

The purpose of this study was to determine the reproducibility of the SGT technique for prevention of XRT-induced xerostomia in a multi-institutional setting and to assess the severity of xerostomia. Quality of life (QOL) outcomes, patterns of recurrence, and disease-free and overall survival rates were also evaluated.

Section snippets

Methods and Materials

A phase II multicenter trial was initiated after the appropriate institutional review board approval was obtained. Viewing of a teaching program on CD-ROM detailing the submandibular SGT procedure was mandatory for all investigators prior to accrual of patients. All simulator films and treatment plans were evaluated centrally by the principal investigator, and surgery was reviewed by 2 reviewers.

Eligibility criteria included biopsy-confirmed squamous cell carcinoma of the oropharynx,

Results

Eight institutions enrolled 49 patients between August 2003 and August 2007. Forty-four patients were analyzable (3 patients were ineligible, and 2 patients received no protocol treatment). Distributions of patients and tumor characteristics are shown in Table 1. Patients were predominantly male (81.8%), Zubrod 0 (79.5%), had oropharynx cancer (63.6%), and were stage IV (61.4%); median age was 56.5 years.

Nine patients (20.9%) developed grade 2 acute xerostomia. In addition, 2 patients had grade

Discussion

Humans produce approximately 600 mL of saliva per day. Parotid secretions are primarily serous and predominate when stimulated during eating, whereas submandibular salivary gland secretions are relatively more mucinous and represent the majority of basal, unstimulated saliva. Parotid secretions contribute only approximately 20% of the total volume of unstimulated saliva, while the submandibular salivary gland contributes 65% and the sublingual 7%-8%. At high flow rates, the parotid glands

Conclusions

The major part of the global burden of head-and-neck cancers is located in the developing world. Even in the cancer centers with no access to IMRT/tomotherapy or other image guided radiation treatment techniques, SGT can be used with standard 3-field techniques for the prevention of XRT-induced xerostomia.

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Supported by Radiation Therapy Oncology Group grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI). The contents of this article are the sole responsibility of the authors and do not necessarily represent the official views of the NCI.

Conflict of interest: none.

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