Diagnostic Accuracy of Ultrasonic Histogram Features to Evaluate Radiation Toxicity of the Parotid Glands: A Clinical Study of Xerostomia Following Head-and-Neck Cancer Radiotherapy

Xerostomia (dry mouth) is a common, often permanent, and debilitating morbidity of radiotherapy (RT) for head-and-neck malignancies (1,2). Patients with severe xerostomia have thick secretions, difficulty in swallowing and speaking, and are at high risk for oral infection and dental caries (3). This symptom burden impairs the quality of life (QoL) of many head-and-neck cancer survivors for months, even years, after treatment (4). It is well established that the main cause of RT-induced xerostomia is irradiation of parotid glands—the major salivary glands producing ~60% of total saliva (1). Recent clinical studies indicate that intensity-modulated radiotherapy (IMRT) provides a significant advantage in sparing the parotid glands and reducing xerostomia. However, even with the new technology, 17%–30% of patients treated with IMRT still develop permanent xerostomia. There is substantial heterogeneity in parotid gland injury after radiation (5–7). In the clinic, radiation-induced xerostomia is assessed using patient-based or physician-based grading systems. For example, the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) established a morbidity scale to evaluate post-RT salivary glands. Specifically, salivary gland toxicity was divided into two categories: acute (≤3 months after RT) toxicity and late (>3 months after RT) toxicity. Physicians assign a score of grade 1 (slight dryness) to grade 4 (necrosis or fibrosis) for acute or late salivary toxicity (8). Such subjective measures of radiation toxicity are prone to intraobserver and interobserver variability. In recent years, many groups have been investigating imaging technologies to evaluate parotid gland injury induced by radiation. Studies using computed tomography (CT), magnetic resonance imaging (MRI), MR sialography, and single-photon emission computed tomography scintigraphy have shown some degree of success in assessing the severity of parotid gland injury and documenting normal tissue response to RT (9–17). However, the high cost, the technical complexity, and the need for dedicated imaging expertise (CT, MRI, or nuclear medicine) preclude their use in routine clinical assessment of xerostomia. The concept of ultrasound imaging to evaluate parotid gland injury is especially attractive because ultrasound is safe, portable, widely available, easy to use, and cost effective. In particular, because parotid glands are superficial structures wrapping around the mandible, they are readily amenable to ultrasound examination. Ultrasound, therefore, is the standard imaging modality in the assessment of salivary gland diseases such as neoplasms, Sjogren syndrome, sialadenitis, and sialolothiasis. However, there is limited information in the literature about evaluation of radiation-induced parotid gland injury or xerostomia using ultrasound (9). Previously, we have proposed an ultrasound technology based on quantitative analysis of echo-intensity histogram to assess RT-associated parotid gland injury (18). A family of sonographic features was derived from the echo histogram to quantify the echogenicity and heterogeneity of parotid glands, which is used to assess the morphologic and architectural integrity of post-RT parotids. In a pilot study of 12 patients, we demonstrated the clinical feasibility of using these echo histogram features in evaluating parotid gland toxicity after RT (18). Another appealing factor of ultrasound histogram evaluation of RT-related parotid gland toxicity is that it could eliminate variations in subjective radiologic interpretations of ultrasound images. To further explore this ultrasound technology in the evaluation of RT-induced parotid gland injury, we embarked on this clinical study. The primary objective was to determine the diagnostic accuracy of echo-intensity histogram parameters in the assessment of RT-induced parotid gland injury. In addition, we compared the quantitative ultrasound examination with radiologists’ evaluation of acute and late toxicities of RT to parotid glands. Special emphasis was placed on acute toxicity for patients within 3 months of cancer treatment. We want to emphasize the importance of developing safe and easy ultrasound technology to detect acute toxicity because early detection of parotid gland injury could enable early interventions to minimize long-term morbidity.