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Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 2, pp. 388 –395, 2007 Copyright © 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter doi:10.1016/j.ijrobp.2006.12.029 CLINICAL INVESTIGATION Head and Neck THE IMPACT OF POSITRON EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY IN EDGE DELINEATION OF GROSS TUMOR VOLUME FOR HEAD AND NECK CANCERS HANI ASHAMALLA, M.D., F.C.C.P.,*† ADEL GUIRGIUS, M.D., M.S.,* EWA BIENIEK, M.D.,* SAMEER RAFLA, M.D.,*† ALEX EVOLA, R.T.(R)(N),† GANESH GOSWAMI, PH.D.,† RANDALL OLDROYD, M.D.,* BAHAA MOKHTAR, M.D.,*† AND KAPILA PARIKH, M.D.*† *Department of Radiation Oncology, New York Methodist Hospital, Weill Medical College of Cornell University, New York, NY; and †Leading Edge Radiation Oncology Services, Brooklyn, NY Purpose: To study anatomic biologic contouring (ABC), using a previously described distinct halo, to unify volume contouring methods in treatment planning for head and neck cancers. Methods and Materials: Twenty-five patients with head and neck cancer at various sites were planned for radiation therapy using positron emission tomography/computed tomography (PET/CT). The ABC halo was used in all PET/CT scans to contour the gross tumor volume (GTV) edge. The CT-based GTV (GTV-CT) and PET/CT-based GTV (GTV-ABC) were contoured by two independent radiation oncologists. Results: The ABC halo was observed in all patients studied. The halo had a standard unit value of 2.19 ⴞ 0.28. The mean halo thickness was 2.02 ⴞ 0.21 mm. Significant volume modification (>25%) was seen in 17 of 25 patients (68%) after implementation of GTV-ABC. Concordance among observers was increased with the use of the halo as a guide for GTV determination: 6 patients (24%) had a <10% volume discrepancy with CT alone, compared with 22 (88%) with PET/CT ( p < 0.001). Interobserver variability decreased from a mean GTV difference of 20.3 cm3 in CT-based planning to 7.2 cm3 in PET/CT-based planning ( p < 0.001). Conclusions: Using the “anatomic biologic halo” to contour GTV in PET/CT improves consistency among observers. The distinctive appearance of the described halo and its presence in all of the studied tumors make it attractive for GTV contouring in head and neck tumors. Additional studies are needed to confirm the correlation of the halo with presence of malignant cells. © 2007 Elsevier Inc. PET/CT planning, Head-and-neck cancers, GTV contouring, Anatomic biologic halo. Positron emission tomography (PET) with the glucose analog 18F-fluoro-2-deoxy-D-glucose (FDG) is a functional imaging method that detects areas of increased glucose metabolism. Because neoplastic cells overexpress glucose transporters and are, therefore, characterized by increased glucose uptake, most neoplastic tissues can be detected by PET. The fusion of PET with computed tomography (PET/ CT) adds anatomic information to the physiologic information of PET, thus allowing for improvement in spatial resolution. The role of PET/CT scan in detecting and staging head and neck cancers is reported in several publications (1–10). The sensitivity and specificity of PET/CT in this disease varies from 67% to 100% (1–10). There is still controversy regarding contouring methods for radiation treatment planning. Riegel et al. (11) recently reported significant variation in the delineation of gross tumor volume (GTV) using PET/CT. They concluded that the varia- tions were due to a lack of consensus about contouring protocol. One of the reasons for these inconsistencies is the controversy among institutions regarding how to define the threshold of malignant disease according to physiologic imaging. In a recent publication, we described a halo phenomenon observed in 19 patients with lung cancer (12). The halo was recognizable by a specific color, slim wall, low standard unit value (SUV) uptake, and its location around the areas of the maximum metabolic activity of the tumor. We also described the anatomic biologic contour (ABC), representing the volume contoured based on PET/CT images, and the counterpart of GTV contoured using CT alone. We showed that use of the halo in delineating GTV resulted in a reduction of interobserver variability, as well as a modification of GTV in 53% of cases when compared with CT-based planning. This halo may serve as a useful tool to unify the contouring of volumes among observers. Reprint requests to: Hani Ashamalla, M.D., F.C.C.P., 506 Sixth Street, Brooklyn, NY 11215. Tel: (718) 780-3677; Fax: (718) 780-3688; E-mail: [email protected] Conflict of interest: none. Received Oct 30, 2006, and in revised form Dec 6, 2006. Accepted for publication Dec 7, 2006. INTRODUCTION 388 Head and neck cancers: PET/CT treatment planning As reported in this article, we prospectively studied the utility of the halo-based contouring method, using fully integrated PET/CT planning in a group of head and neck cancer patients. Our objectives were to: (1) study the presence of the anatomic biologic halo in head and neck cancer and its utility in defining a standard treatment volume using PET/CT images, (2) assess the degree of correlation between CT-based GTV (GTV-CT) and the corresponding PET/CT-based ABC treatment volumes (GTV-ABC), and (3) evaluate the magnitude of interobserver (radiation oncologist) variability in the delineation of GTV-ABC compared with that of GTV-CT treatment volumes. METHODS AND MATERIALS PET/CT simulation protocol We used the GE Discovery ST (GE Healthcare, Waykesher, WI) which combines a light-speed CT 16-slice, in-line with PET bismuth germinate oxide detectors. Ordered subset expectation maximization was used for the reconstruction algorithm. Slice smoothing was performed by posterior filter (5.14 mm) and loop filter (4.69 mm), and the slice thickness was 3.75 mm. Full width at half maximum for 1 cm was 4.8 mm and for 10 cm was 6.3 mm. Three cross-laser pointers and a flat-topped table were integrated with the machine for simulation purposes. Thermoplastic or vacuummolded immobilization devices needed for conformal radiotherapy were custom fabricated. Patients were injected with a standard dose of 10 mCi FDG and left in the designated “quiet room” in the radiation oncology suite for an uptake period of 1 hour. Then, patients were escorted to the PET/CT scanner in the adjacent room (10 feet) and placed on the PET/CT machine in the treatment position, using the previously constructed immobilization devices. For the sake of reproducibility, an anterior and two lateral reference points were tattooed on the patient, using the laser crossmarks. A full-body PET/CT scan was then performed. The scan was electronically transmitted to Xeleris (GE Healthcare) and Eclipse (Varian Medical Systems, Palo Alto, CA) treatment-planning work stations. Coregistration was performed automatically. Fused PET/CT images were adjusted to a window of 35,000 Bq/mL, whereas the level was adjusted at 30,000 Bq/mL; these parameters resulted in a major concordance between the treatmentplanning images and the PET/CT scan without the need to vary the PET threshold. Treatment volume determination Each FDG-PET study was reviewed with the interpreting nuclear radiologist before tumor volumes were contoured. To compare CT-based treatment planning with PET/CT-based planning, treatment volumes were contoured independently by two radiation oncologists. Blinded to the results of PET, the physicians first contoured the GTV from the CT data sets. The GTV-CT volumes included anatomically abnormal and contrast-enhancing regions, as well as lymph nodes ⬎1 cm. The contrast-enhancing regions were delineated using slice-by-slice comparison of the simulation CT with the diagnostic contrast-CT performed before the simulation procedure. Clinical, endoscopic, and other radiologic studies (e.g., magnetic resonance imaging [MRI]) were used in refining the GTV. The GTV-ABC was then contoured separately using fully fused PET/CT imaging. The GTV-ABC included PET-enhancing tumor and gross anatomic lesions, as well as any lymph ● H. ASHAMALLA et al. 389 node with an average SUV of ⱖ2.5, regardless of any deficiency in adequate nodal size criteria for malignancy as visualized by CT images alone. The anatomic biologic halo was recognized as the edge to be used for delineation of the GTV-ABC. An assessment of the degree of correlation between GTV-ABC and GTV-CT was then performed, and interobserver variability was estimated. Additionally, to compare pre- and posttherapy values, we recorded the anatomic biologic value (ABV), defined as the product of mean SUV multiplied by the diameter of GTV-ABC. Patients Twenty-five patients with head and neck cancers were studied. The studied tumors included 6 oropharynx, 4 nasopharynx/paranasal sinus, 4 supraglottis, 4 lymph nodes with unknown primary, 3 oral cavity, 2 thyroid, 1 hypopharynx, and 1 parotid. Median age was 68 years (range, 57– 81 years). Patient characteristics are listed in Table 1. Intensity-modulated radiotherapy was used in 14 patients; the remaining patients were treated with standard radiation techniques. Statistical considerations The values of GTV-CT and GTV-ABC and the mean of planned treatment volumes were recorded. The absolute differences of planned treatment volumes between the two observers were computed. Wilcoxon signed rank tests and sign tests for numeric parameters were used, whereas chi-square or Fisher’s exact tests were used for categoric data. For numeric parameters, the mean values are given ⫾ 1 SD. SAS (SAS Institute, Cary, NC) and STATA (Stata Corp., College Station, TX) software packages were used for statistical analysis. RESULTS Significance of the anatomic biologic halo in defining a standard edge for GTV delineation in radiation treatment planning for head and neck tumors The same halo that we previously described in lung cancer cases (12) was observed around areas of maximal Table 1. Patient characteristics No. of patients Age (y) Median Range Gender Male Female Tumor location Oropharynx Nasopharynx/paranasal sinus Lymph nodes of unknown primary Supraglottis Oral cavity Thyroid Hypopharynx Parotid Stage II III IV 25 68 57–81 16 9 6 4 4 4 3 2 1 1 6 9 10 Data are number of patients, unless otherwise specified. 390 I. J. Radiation Oncology ● Biology ● Physics Fig. 1. Anatomic biologic halo. Intense 18F-fluoro-2-deoxy-D-glucose uptake in nasopharyngeal carcinoma demonstrating the halo phenomenon in two color maps. (a) Computed tomography perfusion; (b) hot iron. SUV uptake in all of the patients with head and neck tumors included in this study. The identification of the halo was made on the basis of its characteristic blush, which was observed around the areas of the highest Volume 68, Number 2, 2007 metabolic activity, regardless of the color map used (Fig. 1). The mean halo thickness was 2.02 ⫾ 0.21 mm (median, 1.2 mm; range, 1.7–2.4 mm). In addition, we observed a gradual decrease in tumor metabolic activity in all of the studied head and neck lesions. The highest SUV registered in the center of the tumor, with the values steadily decreasing toward the periphery. The mean halo SUV was 2.19 ⫾ 0.28 (median, 2.3; range, 1.6 –2.9). The distinct appearance of the halo, its relatively uniform thickness, characteristic color, and low SUV uptake were used to define the edge of the GTV-ABC. Table 2 demonstrates the diameter of each patient’s GTV-ABC volume, the maximum and mean SUV of each contoured volume with the corresponding halo thickness, and unit value reading. The halo SUV as a percentage of the maximum (halo intensity level) and mean SUV are also shown. The mean halo intensity level was 24% ⫾ 13.06%. The median halo intensity level was 19.2%. Table 2. Anatomic biologic halo parameters in head-and-neck cancer patients Case no. Diagnosis ABC diameter (cm) Max SUV Mean SUV Halo thickness (mm) Halo SUV Halo intensity level* ABC diameter ⫻ mean SUV 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Max sinus Nasopharynx Nasopharynx Ethmoid Parotid Hypopharynx Supraglottis Supraglottis Supraglottis Supraglottis Oropharynx Oropharynx Oropharynx Oropharynx Oropharynx Oropharynx LN† LN† LN† LN† Oral cavity Oral cavity Oral cavity Thyroid Thyroid 6.1 5.7 2.3 1.7 4.9 3.1 4.1 3.4 8.3 2.3 1.3 2.8 5.7 1.4 4.7 4.9 7.3 1.2 5.3 2.5 5.8 6.0 7.3 2.6 2.5 12.6 12 9.6 7.7 8.7 13 14.3 14 20.7 4.8 5.5 9.6 14 4.4 17.8 5.7 23.3 4.9 12.8 10.1 4.7 20 23.2 6 6.7 10 8.5 7 6.5 7.2 10.4 11.3 9.8 16 4.2 4.5 7.5 12.5 4.0 15.5 5.0 21.5 4.7 11 8.5 4.5 17 19.8 4.5 6.0 2.3 1.9 2 1.7 1.9 1.8 2.2 1.9 2.1 2.1 2.2 1.8 1.9 1.9 1.9 1.9 2.1 2.2 2.1 2.2 1.9 2.2 2.1 1.7 2.4 1.8 2.3 2.7 2.3 2.3 2.1 2.6 2.4 2.0 2.2 2.1 2.5 2.3 2.3 2.4 2.2 2.6 2.4 2.4 2.1 2.5 1.9 2.6 1.9 2.1 14.3 19.2 28.1 29.9 26.4 16.2 18.2 17.1 9.7 45.8 38.2 26 16.4 5.2 13.5 38.6 11.2 48.9 18.8 20.8 53.2 9.5 11.2 31.7 31.3 61 48.6 16.1 11 35.3 32.3 46.3 33.3 132.8 9.6 5.9 21 71.3 5.6 72.9 24.5 157 5.6 58.3 21.3 26.1 102 144.5 11.7 15 Abbreviations: ABC ⫽ anatomic biologic contouring; SUV ⫽ standard unit value. * Halo intensity level ⫽ halo SUV as a percentage of maximum target SUV. † Lymph nodes with unknown primary. Fig. 2. (a) Oropharyngeal cancer demonstrating modified computed tomography (CT)-based gross tumor volume (GTV) (yellow) and positron emission tomography (PET)/CT-based anatomic biologic contouring (ABC) (green). (b) Baseof-tongue cancer; CT-GTV (red), PET/CT-ABC (blue). (c) Floor-of-mouth cancer; CT-GTV (red), PET/CT-ABC (blue). (d) Floor-of-mouth cancer; CT-GTV (yellow), PET/CT-ABC (green). (e) Nasopharyngeal cancer; CT-GTV (yellow), PET/CT-ABC (green). Head and neck cancers: PET/CT treatment planning ● H. ASHAMALLA et al. 391 392 I. J. Radiation Oncology ● Biology ● Physics Impact of PET/CT-based edge delineation on volume modification Overall (ⱖ25%) modification of GTV using PET/CT planning vs. CT-based planning was seen in 17 of 25 patients (68%). Of these 17, 11 demonstrated reduction in the GTV-CT. The reason for volume reduction was overstated lymph nodes in 9 cases (6 on the opposite side, and 3 on the same side), and the other 2 patients had volume reduction due to inclusion of postoperative scarring. Six patients demonstrated increase in volume with PET/CT; in 4 this was owing to unrecognized contralateral lymph nodes and in 2 to unsuspected base of skull involvement. Figure 2 shows modification of GTV using PET/CT planning in various neck cancer sites. Influence of GTV-ABC contouring on interobserver variability The use of the proposed halo-based contouring approach resulted in significant decrease in variability of GTV outlines done by the two physicians. The amplitude of difference in GTV-CT and GTV-ABC is illustrated in Fig. 3. The differences between the two observers using CT and PET/CT in planning are further illustrated in a box plot in Fig. 4. Interobserver GTV variability decreased from a mean volume difference (mean of sum of differences between the two volumes) of 20.3 cm3 (in CT-based planning) to 7.2 cm3 (in PET/CT-based planning), with a respective decrease in SD from 17.1 to 7.9 ( p ⬍ 0.001). Regression analysis (Fig. 5) demonstrates that if the absolute difference between two observers using CT planning is 1 cm3, then the absolute difference between the same two observers using PET/CT is only 0.34 cm3 (95% confidence interval [CI], 0.21– 0.47). The variations in treatment volumes between observers using CT alone is illustrated in Fig. 6a, and the concordance in delineating ABC by using PET/CT is demonstrated in Fig. 6b. DISCUSSION The integration of PET and CT scans allows the simultaneous utilization of biologic and anatomic imaging data. Although anatomic information obtained from CT has been routinely used as a part of radiation treatment planning, the use of functional images for planning and contouring of the tumor volume remains to be standardized. Part of the current controversy stems from interinstitutional variability in defining the threshold for delineating malignant disease according to physiologic images. Application of different guidelines for tumor volume delineation can result in profound differences in the contouring of final target volumes. Some have arbitrarily advocated the FDGavid volume as the region encompassed by the 50% intensity level relative to the tumor maximum intensity (13–17), whereas Bradley et al. (18) used the 40% intensity level. In an editorial, Paulino and Johnstone (19) suggested autocontouring of all areas with an SUV of 2.5. Scarfone et al. (20) observed that the threshold of PET images needed to be adjusted on a case-by-case basis to adequately depict FDG- Volume 68, Number 2, 2007 Fig. 3. Magnitude of changes in computed tomography– based gross tumor volume (GTV-CT) and anatomic biologic contouring– based GTV (GTV-ABC) among observers of head and neck cancer patients. avid disease relative to the background. In a similar study (11) of 16 head-and-neck cancer patients, four observers contoured GTV in CT and PET/CT images. Significant variation across physicians’ PET/CT volumes was observed ( p ⫽ 0.0002). The investigators concluded the need for a unified contouring protocol for PET/CT treatment planning. We recently reported (12) on the use of PET/CT as a treatment planning tool for lung cancer. We advocated the use of the anatomic biologic volume to represent the contoured GTV when PET/CT is used. A halo was found without the need to vary the PET threshold in all 19 lung cancer patients studied. Having adjusted the window and level to 35,000 and 30,000 Bq/mL, respectively, the halo was used to contour the PET/CT-based GTV with a decrease in interobserver GTV variability from a mean volume difference of 28.3 cm3 (in CT-based planning) to 9.12 cm3 (in PET/CT-based planning) ( p ⬍ 0.0001), with a respective decrease in SD from 20.99 to 6.47. The same halo phenomenon was also true in 25 headand-neck cancer patients studied. The mean SUV of the halo was 2.19 ⫾ 0.28 (range, 1.6 –2.9) at the peripheral edge of the ABC. This relatively low SUV at the edge of PET-based GTV is ⬍2.5, the currently accepted value for detecting malignancy, which has a sensitivity, specificity, and accuracy of 97%, 82%, and 92%, respectively (21). The anatomic biologic halo was detected with a mean thickness of 2.02 ⫾ 0.21 mm (range, 1.7–2.4 mm). The same halo phenomenon was also observed in abdominopelvic sites. The latter will be discussed in a separate work. The halo thickness and SUV reading in lung, head-and-neck, and abdominopelvic sites were found to be consistent (Table 3). Such consistency and reproducibility may, therefore, indicate use of the halo as a potential standardized method for contouring. The main weakness in this work, as well as in similar studies, is the lack of histopathologic confirmation. While these confirmatory studies are desperately awaited, indirect proofs of the specificity of PET/CT as a potential planning tool were offered by Schwartz et al. (7). Twenty patients had preoperative CT scans and PET/CT images before neck dissection. The agreement between the imaging results and pathology findings of neck dissection was stronger for Head and neck cancers: PET/CT treatment planning Fig. 4. Box plot of the differences among observers using computed tomography (CT) and positron emission tomography (PET)/CT scans. FDG-PET/CT (, 0.95; 95% CI, 0.82– 0.99) than for CT alone (, 0.81; 95% CI, 0.63– 0.91; p ⫽ 0.06), indicating that FDG-PET/CT is superior to CT alone for geographic localization of diseased neck node levels. Other studies continued to show the superiority of PET/CT as a planning tool. Ciernik et al. (22) evaluated the feasibility of integrated PET/CT in radiation planning. Among 39 patients with solid tumors studied, 12 were of head and neck origin. The addition of overlay PET data significantly modified the target volume in 6 of them. Daisne et al. (23) studied 30 patients with oropharyngeal cancers who underwent MRI and PET coregisteration with CT planning images. There was significant modification of the target volume in 37%. Nishioka et al. (24) observed higher detection of involved nodes; 39 nodes were detected by PET/CT, compared with only 28 by clinical examination and CT/MRI in 21 patients with nasopharyngeal or oropharyngeal cancers. Nodal target volume was increased in 4 of them (19%). Furthermore, parotid sparing was more feasible in 71% of patients after reducing target volume accord- Fig. 5. A scatter plot of the correlation between computed tomography (CT) and positron emission tomography (PET)/CT differences among observers, with the regression line and the 95% confidence intervals. ABC ⫽ anatomic biologic contouring; GTV ⫽ gross tumor volume. ● H. ASHAMALLA et al. 393 Fig. 6. The variation in treatment volumes between observers using computed tomography (CT) alone (a) vs. positron emission tomography/CT (b) for planning. ing to PET/CT planning. At 18-month follow-up, no recurrences were seen. Koshy et al. (21) studied 36 patients with intact primary head and neck cancers, using PET/CT as part of treatment planning. Radiotherapy volume and dose were altered in 5 patients (14%) and 4 patients (11%), respectively. Wong and Saunders (25) evaluated 17 patients with neck cancers using PET/CT images, which resulted in modification of the radiation therapy plan in 53% of cases. Interobserver variability was addressed by several investigators. Ciernik et al. (22) reported that the mean difference in GTV with CT alone was 26.6 cm3, compared with a mean difference of only 9.1 cm3 with PET/CT. Syed et al. (26) demonstrated that FDG-PET planning has resulted in an improvement of the interobserver degree of confidence in anatomic localization of 51%. They noted that interobserver agreement in assigning primary and nonprimary lesions to anatomic territories was moderate with FDG-PET alone ( coefficients of 0.45 and 0.54, respectively) but almost perfect with FDG-PET/CT ( coefficients of 0.90 and 0.93, respectively). There is considerable variation among investigators in defining the edge of PET/CT-based GTV. Other investigators have used 40 –50% of the maximum SUV intensity levels as the edge of GTV (15–18). We defined halo intensity level as the percentage ratio of halo SUV to the maximum SUV (Table 2). The mean of this value in 25 patients was 24%. Therefore, using the halo to define the GTV edge encompasses the previously proposed PET/CT-based contouring techniques. In addition, it includes all areas with an SUV of 2.5, which reportedly corresponds to threshold of malignancy (21). In this work, a clinically significant (ⱖ25%) modification of GTV was observed in 17 of 25 patients (68%). The concordance among two observers, defined as the percentage of cases that had ⱕ10% volume discrepancy relative to the mean treatment volumes, was increased from 24% with CT-based planning to 88% with PET/CT planning ( p ⬍ 0.001). The mean absolute volume difference was reduced from 20.3 cm3 (in CT-based planning) to 7.2 cm3 (in PET/CT-based planning), with a respective decrease in SD from 17.1 to 7.9 ( p ⬍ 0.001). There are two reasons for the reduction in observer 394 I. J. Radiation Oncology ● Biology ● Physics Volume 68, Number 2, 2007 Table 3. Consistency of anatomic biologic halo in different sites Site No. of patients Halo thickness (mm)* Halo SUV (mm)* Lung Head and neck Abdominopelvic 20 25 16 2.03 ⫾ 0.22 (1.5–2.5) 2.02 ⫾ 0.21 (1.7–2.4) 1.9 ⫾ 0.14 (1.7–2.1) 1.98 ⫾ 0.19 (1.5–2.3) 2.19 ⫾ 0.28 (1.6-2.9) 2 ⫾ 0.17 (1.6–2.3) Abbreviation: SUV ⫽ standard unit value. * Mean ⫾ SD (range). discrepancies. First, the use of PET/CT in treatment planning, as illustrated by others, reduces ambiguities in target delineation. The second plausible reason is the application of the halo in delineation of the GTV edge. The halo’s characteristic hue, relatively uniform SUV, and small thickness make it a clearly identifiable edge around the regions of maximum uptake. This in turn allows for improved reproducibility in gross tumor edge delineation between independent observers. CONCLUSIONS Positron emission tomography/computed tomography planning is a promising tool for refining traditional treat- ment volumes for radiotherapy for head and neck cancer. The ABC is advocated to replace CT-based GTV because it combines data about both anatomy and function of lesions. The characteristic appearance of the halo, with its thin wall and low SUV, provides excellent parameters for future standard use for contouring. Its use in treatment planning resulted in overall alteration of GTV in 68% of patients. In addition, interobserver variability is significantly reduced when an ABC-based definition of GTV is used. 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