The Role of PET-CT Fusion in Head and Neck Cancer

Due to the complex anatomy of the head and neck, imaging of tumors in this region can be challenging. As a result, physiologic imaging using positron-emission tomography (PET) has proven to be a valuable complement to conventional anatomic imaging. Recently, the combination of PET with computed tomography (CT) has been shown to be superior to single-modality imaging in lung cancer.[1] In this manuscript, we review all available literature regarding the use of fused PET-CT imaging for tumors of the head and neck. PET-CT Fusion PET is a physiologic imaging modality that characterizes different tissues in the body according to metabolism.[ 2,3] In contrast, CT and magnetic resonance imaging (MRI) are anatomic imaging modalities. When sufficiently large, tumors can also distort surrounding structures and, as a result, can be detected with anatomic imaging. Therefore, the integration of PET and CT allows for accurate description of a malignancy based on information from two separate tumor characteristics. Anatomic and physiologic images can be fused by two methods: hardware and software. Hardware fusion uses a combined PET-CT scanner. The software technique uses anatomic landmarks to coregister images from separate CT or MRI scanners to the images acquired from PET. Currently, the software technique is more common because it is less expensive and more readily available.[4] Several radioactive tracers can be used to image metabolically active tissues in physiologic imaging. Currently, the most commonly used tracer with PET is 18-fluorodeoxyglucose (FDG). FDG is a radioactively labeled glucose analog that is taken up by tissue in the same fashion as normal glucose, thus becoming concentrated in cells with high glucose utilization. Single-photon emission computed tomography (SPECT), the predecessor of PET, uses FDG or technetium-99m methoxyisobutylisonitrile (Tc-MIBI) as tracers. Tc-MIBI is a cationic and lipophilic molecule that accumulates tissues with high mitochondrial content, including neoplastic cells and myocardium.[5,6] Tc-MIBI SPECT and FDG-PET have been compared in head and neck cancer. Kao et al reported improved detection of recurrent nasopharyngeal carcinoma with FDG-PET over Tc-MIBI SPECT.[5] Similarly, Henze et al described superior detection rates of primary hypopharyngeal and laryngeal carcinomas using FDG-PET over Tc-MIBI SPECT.[7] Detection and Staging of Head and Neck Cancer Primary Tumors
Numerous studies have established the value of FDG-PET in the initial work-up of head and neck cancer. Martino et al reported that FDG-PET had a sensitivity of 95% and specificity of 92% in the initial detection of head and neck tumors.[8] Stokkel et al reported a similar sensitivity and specificity in the detection of lymph node metastasis.[9] More recently, studies have evaluated the role of coregistered PET-CT imaging in the detection and staging of primary tumors. Lardinois et al described the superiority of integrated PET-CT in tumor-node-metastasis (TNM) staging of non-small-cell lung carcinoma.[ 1] Several studies have also evaluated fused PET-CT in the staging of head and neck cancer, as illustrated in Table 1.[10-12] Hany et al reported that PET-CT correctly staged head and neck cancer in 13 of 14 cases, whereas FDG-PET alone correctly staged only 9 of 14.[10] Other studies report their experience with PET-CT vs PET in the detection of disease. Zimny et al described the sensitivity, specificity, and accuracy of PET-CT in tumor detection as 77%, 82% and 79%, respectively.[ 13] This compared favorably to the sensitivity, specificity, and accuracy of PET alone, described as 74%, 73%, and 74%, respectively. Wolf et al did not report an advantage using image fusion for tumor detection, because both FDG-PET and PET-CT accurately detected tumors in all 17 cases of oral maxillofacial carcinoma.[4] Other studies describe a benefit in the accuracy of detection and staging using fused PET-CT compared to CT or MRI alone. Wolf et al reported that tumors were detected by CT in only 12 of 17 cases, compared to detection in all 17 cases with PET-CT.[4] Wong et al found that PET coregistered with CT or MRI correctly staged head and neck cancer in 17 of 18 patients, compared to correct staging in only 11 of 18 with CT or MRI alone.[11] In addition, Antoch et al reported accurate TNM staging using PET-CT in 7 of 13 patients with head and neck cancer and 10 of 12 patients with cancer of unknown primary. By comparison, MRI correctly staged only 4 of 13 patients with head and neck cancer and 8 of 12 patients with cancer of unknown primary.[12] Table 1 shows that PET-CT correctly staged head and neck cancer in 84% while PET and CT/MRI correctly staged 64% and 56% of patients, respectively. Fused PET-CT has also been shown to be better than anatomic imaging alone in the detection of tumor invasion at specific anatomic sites. Wong et al reported that PET-CT correctly detected tumor invasion at 121 of 124 anatomic landmarks, compared with correct detection in 86 of 124 locations with CT alone.[11] Finally, combined imaging provides an improvement in image interpretation compared to FDG-PET alone. Bar- Shalom et al reported that fused PET-CT led to changes in image interpretation for 12 (32.4%) of 37 sites in the head and neck.[14] In this study, PET-CT correctly characterized two lesions as benign that were initially read as malignant using FDG-PET alone. Furthermore, PET-CT described five lesions as malignant that were considered benign or equivocal on FDG-PET. The change in lesion characterization due to added information from fused PET-CT was correct in six of these seven cases. Moreover, in seven cases, information from PET-CT led to the retrospective discovery of a lesion that was initially missed on PET. Five of these seven were later verified as tumor on biopsy. Recurrent Disease
Several studies have established the efficacy of FDG-PET in recurrent disease. McGuirt et al reported that PET provided a distinct advantage over clinical examination and conventional imaging in the detection of tumor recurrence after RT.[15] Wong et al compared CT or MRI coregistered with FDG-PET to CT or MRI alone in the staging of recurrent disease.[11] This study reports accurate staging in 9 of 10 cases using combined imaging and 8 of 10 using CT or MRI alone. In a second study of 68 patients with head and neck cancer, PET-CT was compared to PET alone with respect to accuracy of diagnosis and impact on patient care.[16] Of the patients analyzed, 16 had newly diagnosed head and neck cancer, 34 had recurrent disease, 8 had cancer of unknown primary, and 10 were being evaluated for residual disease after chemotherapy or radiation. PET-CT images were found to have a 74% better anatomic localization in areas previously treated with surgery or irradiation and 58% better anatomic localization in untreated areas. PET-CT significantly reduced the fraction of lesions judged to be equivocal by 53% and also had a higher accuracy of depicting cancer than did PET (96% vs 90%, P = .03). PET-CT altered patient management in 12 (18%) of the 68 patients and was thought to have a significant impact on patient care. Among the reported limitations of physiologic imaging in recurrent disease is the inaccuracy of FDG-PET in the early follow-up period after treatment. Keyes et al reported a high falsenegative rate (17%) for PET in detecting recurrence 1 month after RT, compared to no false-negatives at 4- and 12-month follow-up scans.[17] PET-CT and RT Planning Advantages of PET-CT
The increased sensitivity and specificity of FDG-PET in the nodal staging of head and neck cancer has been well documented, and the anatomic information added by combined PETCT can lead to even greater accuracy in the staging process. Several studies have evinced a clear role for PET-CT fusion in the management and RT planning of non-small-cell lung cancer.[ 18-23] Fewer data are available regarding the role of PET-CT fusion in patients with head and neck cancer. In three recent studies of patients with head and neck cancer, PET-CT fusion was found to have an impact on RT target delineation.[24-26] In a study of 21 patients with nasopharyngeal or oropharyngeal primaries, Nishioka et al found that PET-CT detected 39 positive nodes in contrast to only 28 nodes detected by clinical exam and CT/MRI. In four patients, nodal status was increased, which had an impact on target delineation. Parotid sparing became possible in 71% of patients whose upper neck areas near the parotid glands were tumor free by PET-CT and except for one patient, no recurrences were seen at 18 months when the PET/CT defined volumes were used as the gross tumor volume.[24] Daisne et al reviewed 10 patients with locally advanced oropharyngeal cancers who had MRI and PET coregistration with CT simulation images. They found that the average gross target volume (GTV) was 37% larger when MRI and PET were coregistered with CT in comparison to CT alone.[25] Ciernik et al performed a study assessing the feasibility of integrated PET-CT in RT planning. These data include a subset of 12 patients with head and neck cancer. Of these patients, six had a significant change (> 25%) in GTV determined using PET-CT compared to the GTV defined by CT alone. The mean change in target volume for the 12 cases was 32%, and the mean change in planning target volume was 20%.[26] PET-CT fusion has also been shown to decrease the amount of intraobserver variability in target volume delineation. Ciernik et al reported a decreased variance in GTV defined by the two radiation oncologists in their study using fused PET-CT. The mean difference in GTV for all tumors in the study using CT alone was reported as 26.6 cm³, compared with a mean difference of only 9.1 cm³ using combined imaging.[26] This represents a 65.8% decrease in intraobserver variability using PET-CT. Because of enhanced detection of regional and distant metastasis, PETCT has the potential for influencing patient staging and clinical management. Detection of regional nodal disease in head and neck cancer patients can significantly alter the radiation fields used in conventional radiation as well as the target volumes and ultimate doses of intensity-modulated radiation therapy (IMRT). The detection of distant metastasis by PET-CT can change the intent of treatment (from curative to palliative) and the type of treatment that a patient ultimately receives (ie, chemotherapy alone and not chemoradiation). In the future, the use of PETCT in patients with head and neck cancer may lead to more accurate staging and more precise target volume delineation and consequent radiotherapy volumes and doses. Emory University Experience
At our institution, we have analyzed the influence of FDG-PET-CT fusion on the management of patients with head and neck cancer. Since July 2002, PET-CT fusion has been an integral component of RT planning for our head and neck cancer patients, who are routinely treated with IMRT. Thus far, we have analyzed 36 patients with head and neck cancer who have been treated with IMRT and received PET-CT fusion as part of their treatment planning. This group included 8 women and 28 men with a mean age of 56 years. Primary site location was the oropharynx in 17 cases, nasopharynx in 5, larynx in 4, paranasal sinuses in 3, oral cavity in 2, and hypopharynx in 2, while 3 patients had unknown primaries. Three of these patients underwent neck dissections before chemoradiation. Platinum-based chemotherapy was given concurrently with RT in 31 (86%). Changes in TNM score, American Joint Committee on Cancer (AJCC) stage, and management were noted in 13 (36%), 5 (14%), and 9 (25%) patients, respectively, based on PET-CT findings. PET-CT data upstaged AJCC stage in four and downstaged AJCC stage in one patient. RT volume and dose were altered in 5 (14%) and 4 (11%) patients, respectively, while a change in chemotherapy management occurred in 3 (8%). Five patients initially presented with cancer of unknown primary, and PET data confirmed oropharyngeal primaries in two of these patients. Two patients were found to have distant disease, and management goals were changed from curative to palliative. PET data also detected the presence of a synchronous primary lung cancer in one patient. In the majority of patients, the PETdefined GTV was noted to be congruent with and significantly smaller than the CT-defined GTV. Figures 1 and 2 illustrate the PET- and CT-GTV of a left neck node metastasis and corresponding dose-volume histogram in a patient with oropharyngeal cancer, while Figures 3 and 4 display the PETand CT-GTV of the primary tumor and corresponding dose-volume histogram in a patient with tonsillar cancer. The dose-volume histograms in Figures 2 and 4 are based on inclusion of only the CT-defined GTV in the planning tumor volume. We are currently evaluating whether the differences between PET- and CT-defined GTV have an impact on dose distribution. Limitations of PET-CT
Limitations to the use of PET-CT fusion in RT planning include the quality of image fusion between the CT and PET-CT scans, consistency of target delineation with PET by visual determination and not by using an isointensity level or standardized uptake value, patient movement during the combined PET-CT procedure, and patient position being different between the CT simulation and the PET-CT. In addition, for head and neck patients, the presence of dental metallic implants or nonremovable bridgework can cause artifacts in attenuation-corrected images using the CT scan obtained with a combined PET-CT camera, and therefore, it is recommended that the non- attenuation-corrected PET images also be evaluated.[27] At our institution, the quality of image fusion between CT and PET-CT images is evaluated subjectively by using three anatomic reference points in the head and neck for the registration process. An error of 5 mm between the fused images is the upper limit for what is considered an acceptable registration, and a discrepancy of 2 to 3 mm is the standard for most of our fused images. This may have a slight impact on the determination of GTV based on PET-CT. In a study of four patients with head and neck cancer, coregistration accuracy between MRI, PET, and CT ranged from 1.2 to 4.6 mm and was found to be highly consistent and reproducible among observers.[28] Conclusions Integrated PET-CT combines physiologic and anatomic imaging to better define malignant disease. In the case of head and neck cancer, PETCT fusion is superior to FDG-PET or CT/MRI alone in the staging of disease and in distinguishing benign from malignant lesions. Furthermore, PETCT is highly sensitive in the detection of recurrent disease when performed at least 4 months after treatment. The greatest benefit of integrated PET-CT, in our review, is in radiotherapy treatment planning and in the detection of distant metastasis. Information from PET-CT can lead to changes in the target volume and RT doses employed and, hence, may be helpful in decreasing late effects of radiotherapy. PET-CT fusion has also been seen to decrease intraobserver variability of radiotherapy target delineation. The detection of distant disease may change the goal of patient management from cure to palliation. Potential weaknesses of PET-CT include limited availability, poor sensitivity in tumors with low FDG uptake, and reduced accuracy in early followup after radiotherapy. In conclusion, combined PET-CT may offer significant advantages over single-imaging modalities in the staging of initial disease and radiotherapy treatment planning in patients with head and neck cancer.