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Laryngeal edema after radiotherapy in patients with squamous cell carcinomas of the larynx and hypopharynx
Oral Oncology 48 (2012) 853–858
Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Laryngeal edema after radiotherapy in patients with squamous cell carcinomas of the larynx and hypopharynx Ji Seon Bae a, Jong-Lyel Roh a,⇑, Sang-wook Lee b, Sung-Bae Kim c, Jae Seung Kim d, Jeong Hyun Lee e, Seung-Ho Choi a, Soon Yuhl Nam a, Sang Yoon Kim a,f a
Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Asanbyeongwon-gil 86, Songpa-gu, Seoul 138-736, Republic of Korea Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea d Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea e Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea f Biomedical Research Institute, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 27 November 2011 Received in revised form 22 December 2011 Accepted 27 February 2012 Available online 19 March 2012 Keywords: Laryngeal edema Radiotherapy Risk factors Treatments Recurrences 18 F-FDG PET/CT
s u m m a r y Objectives: Significant laryngeal edema (SLE) after radiotherapy for squamous cell carcinoma of the larynx and hypopharynx may be associated with upper airway obstruction or tumor recurrence. We assessed the risk factors predictive of SLE and those differentiating tumor recurrence from SLE. Patients and methods: We evaluated 127 patients with laryngohypopharyngeal squamous cell carcinomas who were primarily treated with radiotherapy with/without chemotherapy, had no previous major head and neck surgery, and underwent laryngoscopic examinations after radiotherapy. SLE was defined as RTOG grades P2 and patient characteristics and imaging, treatment and survival results were compared in patients with and without SLE. Results: Of the 127 patients, 56 (44%) had SLE. Univariate analyses showed that tumor location, T and N classifications, overall stage, pathologic differentiation, and chemotherapy were significantly predictive of SLE (P < 0.05). Multivariate analysis revealed that T classification remained an independent predictor of SLE (T1 vs. T2–4; odds ratio = 5.070, 95% confidence interval = 1.999–12.857; P = 0.001). Twenty-seven (21%) patients had tumor recurrences, diagnosed by PET/CT (sensitivity 88%; specificity 92%) and CT (sensitivity 68%; specificity 88%). Twenty-seven patients with severe SLE were treated but only 9 (33%) had improvement. Tumor recurrence rate was higher (39% vs. 7%, P < 0.001) and 3-year overall survival rate lower (54% vs. 87%, P < 0.001) in patients with than without SLE. Conclusion: Patients with T2–4 laryngohypopharyngeal cancers are at higher risk of SLE development and tumor recurrence after radiotherapy that can be properly detected by 18F-FDG PET/CT. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction Although radiotherapy (RT) of patients with head and neck cancers allows laryngeal preservation, it may induce salivary or laryngopharyngeal dysfunction, affecting patient quality of life. Inflammation, lymphatic disruption and subsequent fibrosis can lead to long-term problems with phonation, swallowing, and breathing.1,2 RT-induced laryngeal edema is a common and expected side effect in patients treated for head and neck cancer, with a continuum extending from absent or mild swelling to severe swelling or chondroradionecrosis.3 Severe laryngeal edema
⇑ Corresponding author. Tel.: +82 2 3010 3965; fax: +82 2 489 2773. E-mail address: [email protected] (J.-L. Roh). 1368-8375/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2012.02.023
may cause upper airway obstruction and require urgent tracheostomy.2 Moderate or severe laryngeal edema can also accompany residual or recurrent cancers, making it difficult to distinguish between tumor recurrence and normal tissue changes after RT.4 Thus, it is important to know both the factors contributing to laryngeal edema and the incidence of residual or recurrent tumors in patients with RT-induced laryngeal edema. In addition, early differential diagnosis of tumor recurrence from laryngeal edema can lead to proper patient management and improve survival outcomes in patients undergoing definitive RT for head and neck cancers. We therefore evaluated (1) the risk factors predictive of significant laryngeal edema (SLE), (2) the factors differentiating tumor recurrence from SLE, and (3) the treatment outcomes of patients who experience severe laryngeal edema after RT for laryngeal or hypopharyngeal cancer.
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Patients and methods Study population We evaluated all patients with squamous cell carcinoma of the larynx or hypopharynx who were treated with RT radiotherapy with/without chemotherapy at Asan Medical Center between 2005 and 2010. Total 343 patients received the diagnosis of laryngeal or hypopharyngeal carcinoma for this study period. Patients with a previous history of head-and-neck malignancies or major surgery in the head and neck region, as well as patients with unresectable tumors, non-squamous cell carcinoma, or distant metastases, were excluded. Patients underwent serial fiberoptic or rigid endoscopic laryngeal examination with photographic documentation (ENF-P4; Olympus Co., Tokyo, Japan) before initial treatment and within 24 months after completion of RT. This study was reviewed and approved by the Institutional Review Board of our hospital. We found that 127 patients met our inclusion and exclusion criteria. All 127 patients received definitive external-beam RT with total cumulative doses of 40–80Gy (median 70Gy) to the laryngeal area in once-daily fractions of 180–200cGy. Of these 127 patients, 2 (2%) underwent intensity-modulated radiotherapy (IMRT) and others underwent conventional external beam RT. Of the patients included, 46 (36%) underwent concurrent chemotherapy with cisplatin and 13 (10%) underwent chemotherapy prior to RT, consisting of cisplatin plus 5-fluorouracil, docetaxel or TS-1.
CT and CT images were read by visual inspection by experienced nuclear medicine physicians and radiologists. The presence of residual or recurrent tumors on imaging was confirmed by biopsy or imaging follow-up. Statistical analysis The grade of laryngeal edema was scored according to the Radiation Therapy Oncology Group (RTOG) scale as 0, no edema; 1, slight edema; 2, moderate edema; 3, severe edema; and 4, necrosis (Figs. 1 and 2).6 Grade 1 corresponds to minimal thickening of the supraglottis, and grade 2 corresponds to more diffuse or evident edema but no significant or symptomatic airway obstruction. The diagnosis of laryngeal edema was performed by two observers, commonly prior to knowing that patients recurred. The change of grades was observed in serial endoscopic examinations and the grading determined was as the worst observed. Patients were divided into two groups, those with (grade P 2) and without (grades 0 and 1) significant laryngeal edema (SLE), as the risk of grade P 2 laryngeal edema was previously presented.7,8 Clinicopathologic variables in the two groups were compared using two-sided Fisher’s exact or v2 test. Multivariate analysis was performed by binary logistic regression of variables with P < 0.05 on univariate analysis. Locoregional control and survival rates were calculated using the Kaplan–Meier method and compared using the log–rank test. Results
Imaging and confirmation of residual or recurrent disease Patients underwent imaging work-up, at initial staging and after treatments, with CT and whole-body 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT. Imaging was performed regularly, particularly within the first 2 years after initial treatment. FDG PET/CT was performed using a Biograph Sensation 16 scanner (Siemens/CTI), according to our standard protocol,5 and contrast-enhanced CT was performed using a Somatom Sensation 16 (Siemens Medical Solutions; Forchheim, Germany). The PET/
This study included 127 eligible patients, consisting of 124 men and 3 women of median age 63 years (range, 30–84 years). The major locations of the primary tumors were the glottis (48%), hypopharynx (36%), supraglottis (12%) and subglottis (4%). Fifty patients (40%) had advanced T3–4 tumors, 52 (41%) had N+, and 68 (54%) had advanced overall stage III or IV tumors. SLE grade P 2 was observed in 56 patients (44%), grade 2 in 27 (21%), grade 3 in 21 (17%), and grade 4 in 8 (6%). The remaining 71 patients had laryngeal edema of grade 0 (n = 43, 34%) or 1 (n = 28, 22%). The
Figure 1 Laryngoscopic view showing laryngeal edema. Grades 0 (A, normal), 1 (B, mild), 2 (C, moderate), and 3 (D, severe) on RTOG classification.
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J.S. Bae et al. / Oral Oncology 48 (2012) 853–858
Figure 2 Computed tomography showing severe laryngeal edema of grades 3 (A) and 4 (B, chondroradionecrosis).
characteristics of patients with and without SLE are summarized in Table 1. On univariate analysis, tumor location, T and N classifications, overall stage, pathologic differentiation, and chemotherapy
were predictive of SLE (P < 0.05 each). On multivariate analysis, T classification remained the only independent factor associated with the development of SLE (P < 0.001). SLE developed
Table 1 Univariate analyses of clinicopathologic characteristics predictive of significant laryngeal edema after radiotherapy. Variable
Total, n (%)
Gender Age, years Alcohol (n = 126)c Smoking (n = 126)c Comorbidity
Second cancer BMI, kg/m2
Albumin, g/dL (n = 123)c Location Laryngeal subsite
T classification
N classification Overall stage
Differentiation (n = 108)c
Chemotherapy c
RT dose, Gy (n = 123)
Male Female 665 >65 Yes No Yes No Diabetes Cardiovascular Pulmonary Yes No <18 18–25 >25 <3.3 P3.3 Larynx Hypopharynx Glottis Supraglottis Subglottis T1 T2 T3 T4 N0 N1–3 I II III IV Well (G1) Moderate (G2) Poorly (G3) Yes No 668 >68
124 (98) 3 (2) 70 (55) 57 (45) 82 (65) 44 (35) 105 (83) 21 (17) 26 (20) 50 (39) 23 (18) 33 (26) 94 (74) 9 (7) 90 (71) 28 (22) 11 (9) 112 (91) 81 (64) 46 (36) 61 (75) 15 (19) 5 (6) 57 (45) 20 (16) 21 (17) 29 (23) 75 (59) 52 (41) 51 (40) 8 (6) 14 (11) 54 (43) 36 (33) 67 (62) 5 (5) 59 (46) 68 (54) 24 (20) 99 (80)
Abbreviations: BMI, body mass index; RT, radiotherapy. a Significant laryngeal edema was defined as grade P 2 by RTOG classification.6 b Assessed using the two-sided Fisher’s exact or v2 test. c Not known in other patients.
Laryngeal edemaa, n (%)
Pb
Grade 0–1
Grade 2–4
71 (57) 0 41 (59) 30 (53) 41 (50) 30 (68) 58 (55) 13 (62) 16 (62) 28 (56) 11 (65) 18 (55) 53 (56) 3 (33) 49 (54) 19 (68) 3 (27) 65 (58) 51 (63) 20 (43) 45 (74) 4 (27) 2 (40) 45 (79) 5 (25) 9 (43) 12 (41) 52 (69) 19 (37) 41 (80) 2 (25) 6 (43) 22 (41) 27 (75) 31 (46) 3 (60) 26 (44) 45 (66) 12 (50) 58 (59)
53 (43) 3 (100) 29 (41) 27 (47) 41 (50) 14 (32) 47 (45) 8 (38) 10 (38) 22 (44) 12 (35) 15 (45) 41 (44) 6 (67) 41 (46) 9 (32) 8 (73) 47 (42) 30 (37) 26 (57) 16 (26) 11 (73) 3 (60) 12 (21) 15 (75) 12 (57) 17 (59) 23 (31) 33 (63) 10 (20) 6 (75) 8 (57) 32 (59) 9 (25) 36 (54) 2 (40) 33 (56) 23 (34) 12 (50) 41 (41)
0.048 0.502 0.050 0.574 0.517 0.986 0.388 0.855 0.169
0.050 0.001 0.002
<0.001
<0.001 <0.001
0.025
0.012 0.446
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Table 2 Tumor recurrences in patients with and without significant laryngeal edema.
a b
Laryngeal edemaa, n (%)
Pb
Variable
N (%)
Grade 0–1
Grade 2–4
Total Sites of recurrences Primary Larynx (n = 81) Hypopharynx (n = 46) Regional Distant Total
127
71 (56)
56 (44)
20 (16) 11 (14) 9 (20) 13 (10) 4 (4) 27 (21)
3 2 1 2 0 5
17 (30) 9 (30) 8 (30) 11 (20) 4 (7) 22 (39)
(4) (2) (5) (3) (7)
<0.001 0.009 0.005 0.002 0.023 <0.001
Defined as grade P 2 by the RTOG classification of laryngeal edema.6 Assessed using the two-sided Fisher’s exact or v2 test.
Table 3 Detection of residual or recurrent tumors in patients with/without laryngeal edema. Imaging
Recurrences Yes
Local (primary sites) PET/CT (n = 113) Yes 15 (TP) No 2 (FN) CT (n = 111) Yes 13 (TP) No 6 (FN) Regional (cervical lymph nodes) PET/CT (n = 113) Yes 10 (TP) No 1 (FN) CT (n = 109) Yes 9 (TP) No 4 (FN)
Total
Table 4 Outcomes of treatments of the 27 patients with severe laryngeal edema. Variable
No
8 (FP) 88 (TN) 13 (FP) 79 (TN)
23 90 26 85
4 (FP) 98 (TN)
14 99
10 (FP) 86 (TN)
19 90
Abbreviations: PET, positron emission tomography; TP, true-positive; FP, falsepositive; FN, false-negative; TN, true-negative; PPV, positive predictive value; NPV, negative predictive value.
significantly more frequently in patients with T2–4 tumors than in those with T1 tumors (odds ratio [OR] = 5.070, 95% confidence interval [CI] = 1.999–12.857; P = 0.001). Of the 127 patients, 27 (21%) had residual or recurrent tumors, 20 at the primary tumor site, 13 at cervical nodes, and four at distant sites (Table 2). Local failure based on T stage was observed 3 of 57 T1 patients (5%), 5 of 20 T2 patients (25%), 4 of 21 T3 patients (19%), and 8 of 29 T4 patients (28%) (P = 0.026). Recurrent tumors were observed in 22 (39%) patients with and 5 (7%) without SLE (P < 0.001). The ability of imaging modalities to detect locoregional
Laryngeal edema Grade 3 Grade 4 Location Larynx Hypopharynx T classification T1–2 T3–4 N classification N0 N+ Treatments Steroid Antibiotics Tracheostomy Hyperbaric oxygen therapy Residual or recurrent tumors Local (n = 11) Regional (n = 6)
Laryngeal edema, n (%)
P
No change
Improveda
12 (60) 6 (86)
8 (40) 1 (14)
8 (67) 10 (67)
4 (33) 5 (33)
7 (70) 11 (65)
3 (30) 6 (35)
6 (60) 12 (71)
4 (40) 5 (29)
13 (62) 17 (71) 16 (80) 2 (100)
8 7 4 0
(38) (29) (20) (0)
0.323 0.250 0.023 0.436
9 (82) 5 (83)
2 (18) 1 (17)
0.226 0.378
0.224
0.660
0.561
0.439
a Defined as grade 6 2 compared with grade 3–4 laryngeal edema on RTOG classification after treatments.
disease is shown in Table 3. FDG PET/CT was performed in 113 patients and correctly evaluated 15 of the 20 patients with local recurrences and 10 of the 13 with regional recurrences (Fig. 3). CT was performed in 111 patients and correctly evaluated 13 of 20 patients with local recurrences and 9 of 13 with regional recurrences. Therefore, the overall sensitivity, specificity, accuracy, and
Figure 3 A case of true-positive PET/CT result for local recurrence. The laryngeal edema on contrast-enhanced CT (A) was correctly interpreted as local recurrence with a focal 18 F-FDG uptake on PET (B) and integrated PET/CT (C) images that was confirmed by biopsy.
J.S. Bae et al. / Oral Oncology 48 (2012) 853–858
positive and negative predictive values (PPV and NPV) of PET/CT for identifying local recurrences were 88%, 92%, 91%, 65%, and 98%, respectively, while those of CT were 68%, 88%, 83%, 50%, and 83%, respectively. The overall sensitivity, specificity, accuracy, PPV and NPV of PET/CT for detecting regional recurrences were 91%, 96%, 96%, 71%, and 99%, respectively, while those of CT were 69%, 90%, 87%, 47% and 96%, respectively. The diagnostic capacity of PET/CT appeared to be higher than that of CT, but statistical differences were not calculated because each of these tests was not performed in all patients. Of 29 patients with severe SLE (grade 3 or 4), 21 were treated with intravenous or oral steroids, 24 were treated with antibiotics, 20 underwent tracheostomy, and 2 received hyperbaric oxygen therapy (Table 4). Tracheostomy was performed in 3 of 57 T1 patients (5%) and 17 of 70 T2–T4 patients (10%) (P = 0.003). We found that severe SLE improved in 9 (31%) patients but remained unchanged in 18 (62%); the other two patients did not undergo proper long-term evaluation after treatment. When we compared the clinical parameters in patients with and without improvements in severe SLE, we observed no significant differences in grades of laryngeal edema, tumor location, T and N classifications, treatment modalities, and rates of locoregional recurrence. The median follow-up time of survivors was 35 months (range, 6–74 months). The 3-year overall survival rate of all patients was 72%, 87% in the non-SLE group and 54% in the SLE group (P < 0.001). Discussion Laryngeal edema is one of the most common side effects of RT for head and neck cancer, with 15–59% of patients with head and neck cancers developing grade P 2 laryngeal edema at least once within 2 years after RT.4,7–9 Dosimetric and normal tissue complication probability (NTCP) models have indicated that laryngeal edema was correlated with mean dose to the larynx P50Gy.3,7,8 When mean laryngeal dose and volume are maintained at <43.5Gy and <27%, respectively, the incidence of laryngeal edema was minimal (<20%).3 We observed SLE in 56 of our 127 (44%) patients, which is within ranges previously reported.4,7,8 We did not detect a relationship between RT dose and laryngeal edema, since 124 (98%) of our patients received a curative RT dose to the larynx, ranging from 62Gy to 80Gy, a dose associated with RT of carcinomas arising in the larynx and hypopharynx. Similar to prior reports,4,9 we found that SLE rate was related to high primary tumor stage. Fibrotic changes following RT may lead to blockade of lymphatic vessels, causing laryngeal edema, particularly in the supraglottic areas, that may correlate with tumor burden and location.4 Lymphatic flow is greater up to the supraglottis or down to the subglottis than in the glottis. Thus, laryngeal edema is more frequently seen in supraglottic and subglottic areas. Furthermore, our univariate analysis showed that SLE incidence was higher in patients with supraglottic and subglottic cancers than in patients with glottic cancers (70% vs. 26%, P = 0.001). We found that T classification was the only factor independently predictive of SLE, with the risk of SLE being greater in patients with T2–4 than in those with T1 tumors (OR = 5.070, P = 0.001). This finding suggests the SLE may be associated with a larger tumor burden prior to RT or with tumors remaining or recurring at the primary tumor site after RT.4,9 Laryngeal edema frequently develops during or shortly after treatment and tends to regress over time.8 Patients with laryngeal edema of grade P 2 may have upper airway obstruction, with some having severe airway obstruction requiring an emergency tracheostomy. Irradiation of the larynx and pharynx with a high RT dose may result in progressive edema and associated fibrosis, leading to long-term problems with phonation and swallowing impairment.3,8 Laryngeal edema may be an early detectable morphologic
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change predicting late functional impairment.8 Persistent edema may be caused by exogenous stimulation, infection, surgical trauma, delayed RT effects, or residual or recurrent tumors.4 Antibiotics or steroids may be used to treat persistent laryngeal edema unresponsive by initial conservative treatment methods, such as discontinuing alcohol, cigarette intake, and voice rest. Hyperbaric oxygen therapy (HBO) has also been utilized to treat radiation necrosis (grade IV laryngeal edema), but its efficacy remains unclear.10,11 We found that these treatment methods contributed to improving edema and symptoms in some of our cases with severe SLE, but we could not identify any factors predictive of improvements. Early reports noted that local recurrences in about 50% of patients were related to persistent laryngeal edema.4,9,12–14 Moreover, laryngeal edema persisting for >3 months may suggest the presence of residual or recurrent tumors.14 We observed residual or recurrent local tumors in 22 of 56 (39%) patients with SLE, with the rate higher in patients who did not show improvements after treatment.4,9,12–14 Because of difficulties distinguishing tumor recurrence from post irradiation changes, frequent biopsies have been recommended to determine whether a residual or recurrent tumor is present.12,13 However, laryngeal biopsy may incite a fulminant perichondritis, leading to chondroradionecrosis, and repeated negative biopsy results cannot exclude the presence of tumors.14 Imaging methods, including CT and/or FDG PET or combined PET/CT, may differentiate between recurrent tumors and laryngeal edema.5,15–17 Recently, FDG PET/CT was shown to have greater sensitivity and specificity than CT in detecting active residual or recurrent diseases after RT or chemoradiotherapy.5,16,17 Indeed, we found that the NPV of FDG PET/CT for detecting viable tumors in the larynx or hypopharynx was as high as 98%, suggesting that repeated biopsies in patients with PET-negative lesions are not necessary. It may be necessary, however, to confirm tumor recurrences in patients with PET-positive lesions in the surrounding laryngeal edema because tumor recurrence rates were higher and survival rates were lower in patients with than without SLE. Our study has the potential limitations of a retrospective study. This may affect the real incidence and outcomes of patients with laryngeal edema and the diagnostic values of imaging modalities. Because all included patients had primary tumors of the larynx or hypopharynx, we could not assess the effects of RT on the uninvolved larynx. In addition, while some lesions interpreted as positive on imaging were histologically confirmed, others were assessed only by imaging workup and/or follow-up imaging. The latter may be useful in oncological practice because not all patients suspected of having recurrent tumors are able to undergo biopsy procedures for pathologic confirmation. In conclusion, we found that a significant proportion of patients with laryngeal or hypopharyngeal carcinomas had SLE after definitive RT. Patients with T2–4 tumors were at a higher risk of SLE than other patients. SLE is frequently associated with residual or recurrent tumors and subsequent low patient survival rates. These patients should be carefully monitored for airway problems, as well as for tumor recurrences, which may be differentially diagnosed from laryngeal edema without viable tumors using FDG PET/CT. Conflict of interest statement None declared. References 1. Fung K, Yoo J, Leeper HA, Hawkins S, Heeneman H, Doyle PC, et al. Vocal function following radiation for non-laryngeal versus laryngeal tumors of the head and neck. Laryngoscope 2001;111:1920–4. 2. Patterson JM, Hildreth A, Wilson JA. Measuring edema in irradiated head and neck cancer patients. Ann Otol Rhinol Laryngol 2007;116:559–64.
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3. Rancati T, Schwarz M, Allen AM, Feng F, Popovtzer A, Mittal B, et al. Radiation dose-volume effects in the larynx and pharynx. Int J Rad Oncol Biol Phys 2010;76:S64–9. 4. Ichimura K, Sugasawa S, Nibu KI, Takasago E, Hasezawa K. The significance of arytenoid edema following radiotherapy of laryngeal carcinoma with respect to residual and recurrent tumour. Auris Nasus Larynx 1997;24: 391–7. 5. Kim SY, Kim JS, Yi JS, Lee JH, Choi SH, Nam SY, et al. Evaluation of 18F-FDG PET/ CT and CT/MRI with histopathologic correlation in patients undergoing salvage surgery for head and heck squamous cell carcinoma. Ann Surg Oncol 2011;18:2579–84. 6. Cox JD, Stetz JA, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–6. 7. Rancati T, Fiorino C, Sanguineti G. NTCP Modeling of subacute/late laryngeal edema scored by fiberoptic examination. Int J Rad Oncol Biol Phys 2009;75:915–23. 8. Sanguineti G, Aadapala P, Endres EJ, Brack C, Fiorino C, Sormani MP, et al. Dosimetric predictors of laryngeal edema. Int J Rad Oncol Biol Phys 2007;68:741–9. 9. Fu KK, Woodhouse RJ, Quivey JM, Philips TL, Dedo HH. The significance of laryngeal edema following radiotherapy of carcinoma of the vocal cord. Cancer 1983;49:655–8.
10. Hao SP, Chen HC, Wei FC, Chen CY, Yeh AR, Su JL. Systematic management of osteoradionecrosis in the head and neck. Laryngoscope 1999;109:13247. 11. Annane D, Depondt J, Aubert P, Villart M, Géhanno P, Gajdos P, et al. Hyperbaric oxygen therapy for radionecrosis of the jaw: a randomized, placebo-controlled, double-blind trial from the ORN96 study group. J Clin Oncol 2004;22:4893900. 12. Milligan C, Goffinet DR, Fee W, et al. Vocal cord carcinoma: the relationship between post-radiotherapy laryngeal edema and local recurrence. Int J Rad Oncol Biol Phys 1976(Suppl. 1);81. 13. Ward PH, Calcaterra TC, Kagan AR. The enigma of post-radiation edema and recurrent or residual carcinoma of the larynx. Laryngoscope 1975;85:5229. 14. Bahadur S, Amatya RC, Kacker SK. The enigma of post-radiation oedema and residual or recurrent carcinoma of the larynx and pyriform fossa. J Laryngol Otol 1985;99(8):7635. 15. Inohara H, Enomoto K, Tomiyama Y, Yoshii T, Osaki Y, Higuchi I, et al. The role of CT and (18)F-FDG PET in managing the neck in node-positive head and neck cancer after chemoradiotherapy. Acta Otolaryngol 2009;129:8939. 16. Passero VA, Branstetter BF, Shuai Y, Heron DE, Gibson MK, Lai SY, et al. Response assessment by combined PET-CT scan versus CT scan alone using RECIST in patients with locally advanced head and neck cancer treated with chemoradiotherapy. Ann Oncol 2010;21:227883. 17. Ong SC, Schöder H, Lee NY, Patel SG, Carlson D, Fury M, et al. Clinical utility of 18 F-FDG PET/CT in assessing the neck after concurrent chemoradiotherapy for Locoregional advanced head and neck cancer. J Nucl Med 2008;49:53240.
Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Laryngeal edema after radiotherapy in patients with squamous cell carcinomas of the larynx and hypopharynx Ji Seon Bae a, Jong-Lyel Roh a,⇑, Sang-wook Lee b, Sung-Bae Kim c, Jae Seung Kim d, Jeong Hyun Lee e, Seung-Ho Choi a, Soon Yuhl Nam a, Sang Yoon Kim a,f a
Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Asanbyeongwon-gil 86, Songpa-gu, Seoul 138-736, Republic of Korea Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea d Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea e Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea f Biomedical Research Institute, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 27 November 2011 Received in revised form 22 December 2011 Accepted 27 February 2012 Available online 19 March 2012 Keywords: Laryngeal edema Radiotherapy Risk factors Treatments Recurrences 18 F-FDG PET/CT
s u m m a r y Objectives: Significant laryngeal edema (SLE) after radiotherapy for squamous cell carcinoma of the larynx and hypopharynx may be associated with upper airway obstruction or tumor recurrence. We assessed the risk factors predictive of SLE and those differentiating tumor recurrence from SLE. Patients and methods: We evaluated 127 patients with laryngohypopharyngeal squamous cell carcinomas who were primarily treated with radiotherapy with/without chemotherapy, had no previous major head and neck surgery, and underwent laryngoscopic examinations after radiotherapy. SLE was defined as RTOG grades P2 and patient characteristics and imaging, treatment and survival results were compared in patients with and without SLE. Results: Of the 127 patients, 56 (44%) had SLE. Univariate analyses showed that tumor location, T and N classifications, overall stage, pathologic differentiation, and chemotherapy were significantly predictive of SLE (P < 0.05). Multivariate analysis revealed that T classification remained an independent predictor of SLE (T1 vs. T2–4; odds ratio = 5.070, 95% confidence interval = 1.999–12.857; P = 0.001). Twenty-seven (21%) patients had tumor recurrences, diagnosed by PET/CT (sensitivity 88%; specificity 92%) and CT (sensitivity 68%; specificity 88%). Twenty-seven patients with severe SLE were treated but only 9 (33%) had improvement. Tumor recurrence rate was higher (39% vs. 7%, P < 0.001) and 3-year overall survival rate lower (54% vs. 87%, P < 0.001) in patients with than without SLE. Conclusion: Patients with T2–4 laryngohypopharyngeal cancers are at higher risk of SLE development and tumor recurrence after radiotherapy that can be properly detected by 18F-FDG PET/CT. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction Although radiotherapy (RT) of patients with head and neck cancers allows laryngeal preservation, it may induce salivary or laryngopharyngeal dysfunction, affecting patient quality of life. Inflammation, lymphatic disruption and subsequent fibrosis can lead to long-term problems with phonation, swallowing, and breathing.1,2 RT-induced laryngeal edema is a common and expected side effect in patients treated for head and neck cancer, with a continuum extending from absent or mild swelling to severe swelling or chondroradionecrosis.3 Severe laryngeal edema
⇑ Corresponding author. Tel.: +82 2 3010 3965; fax: +82 2 489 2773. E-mail address: [email protected] (J.-L. Roh). 1368-8375/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2012.02.023
may cause upper airway obstruction and require urgent tracheostomy.2 Moderate or severe laryngeal edema can also accompany residual or recurrent cancers, making it difficult to distinguish between tumor recurrence and normal tissue changes after RT.4 Thus, it is important to know both the factors contributing to laryngeal edema and the incidence of residual or recurrent tumors in patients with RT-induced laryngeal edema. In addition, early differential diagnosis of tumor recurrence from laryngeal edema can lead to proper patient management and improve survival outcomes in patients undergoing definitive RT for head and neck cancers. We therefore evaluated (1) the risk factors predictive of significant laryngeal edema (SLE), (2) the factors differentiating tumor recurrence from SLE, and (3) the treatment outcomes of patients who experience severe laryngeal edema after RT for laryngeal or hypopharyngeal cancer.
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Patients and methods Study population We evaluated all patients with squamous cell carcinoma of the larynx or hypopharynx who were treated with RT radiotherapy with/without chemotherapy at Asan Medical Center between 2005 and 2010. Total 343 patients received the diagnosis of laryngeal or hypopharyngeal carcinoma for this study period. Patients with a previous history of head-and-neck malignancies or major surgery in the head and neck region, as well as patients with unresectable tumors, non-squamous cell carcinoma, or distant metastases, were excluded. Patients underwent serial fiberoptic or rigid endoscopic laryngeal examination with photographic documentation (ENF-P4; Olympus Co., Tokyo, Japan) before initial treatment and within 24 months after completion of RT. This study was reviewed and approved by the Institutional Review Board of our hospital. We found that 127 patients met our inclusion and exclusion criteria. All 127 patients received definitive external-beam RT with total cumulative doses of 40–80Gy (median 70Gy) to the laryngeal area in once-daily fractions of 180–200cGy. Of these 127 patients, 2 (2%) underwent intensity-modulated radiotherapy (IMRT) and others underwent conventional external beam RT. Of the patients included, 46 (36%) underwent concurrent chemotherapy with cisplatin and 13 (10%) underwent chemotherapy prior to RT, consisting of cisplatin plus 5-fluorouracil, docetaxel or TS-1.
CT and CT images were read by visual inspection by experienced nuclear medicine physicians and radiologists. The presence of residual or recurrent tumors on imaging was confirmed by biopsy or imaging follow-up. Statistical analysis The grade of laryngeal edema was scored according to the Radiation Therapy Oncology Group (RTOG) scale as 0, no edema; 1, slight edema; 2, moderate edema; 3, severe edema; and 4, necrosis (Figs. 1 and 2).6 Grade 1 corresponds to minimal thickening of the supraglottis, and grade 2 corresponds to more diffuse or evident edema but no significant or symptomatic airway obstruction. The diagnosis of laryngeal edema was performed by two observers, commonly prior to knowing that patients recurred. The change of grades was observed in serial endoscopic examinations and the grading determined was as the worst observed. Patients were divided into two groups, those with (grade P 2) and without (grades 0 and 1) significant laryngeal edema (SLE), as the risk of grade P 2 laryngeal edema was previously presented.7,8 Clinicopathologic variables in the two groups were compared using two-sided Fisher’s exact or v2 test. Multivariate analysis was performed by binary logistic regression of variables with P < 0.05 on univariate analysis. Locoregional control and survival rates were calculated using the Kaplan–Meier method and compared using the log–rank test. Results
Imaging and confirmation of residual or recurrent disease Patients underwent imaging work-up, at initial staging and after treatments, with CT and whole-body 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT. Imaging was performed regularly, particularly within the first 2 years after initial treatment. FDG PET/CT was performed using a Biograph Sensation 16 scanner (Siemens/CTI), according to our standard protocol,5 and contrast-enhanced CT was performed using a Somatom Sensation 16 (Siemens Medical Solutions; Forchheim, Germany). The PET/
This study included 127 eligible patients, consisting of 124 men and 3 women of median age 63 years (range, 30–84 years). The major locations of the primary tumors were the glottis (48%), hypopharynx (36%), supraglottis (12%) and subglottis (4%). Fifty patients (40%) had advanced T3–4 tumors, 52 (41%) had N+, and 68 (54%) had advanced overall stage III or IV tumors. SLE grade P 2 was observed in 56 patients (44%), grade 2 in 27 (21%), grade 3 in 21 (17%), and grade 4 in 8 (6%). The remaining 71 patients had laryngeal edema of grade 0 (n = 43, 34%) or 1 (n = 28, 22%). The
Figure 1 Laryngoscopic view showing laryngeal edema. Grades 0 (A, normal), 1 (B, mild), 2 (C, moderate), and 3 (D, severe) on RTOG classification.
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Figure 2 Computed tomography showing severe laryngeal edema of grades 3 (A) and 4 (B, chondroradionecrosis).
characteristics of patients with and without SLE are summarized in Table 1. On univariate analysis, tumor location, T and N classifications, overall stage, pathologic differentiation, and chemotherapy
were predictive of SLE (P < 0.05 each). On multivariate analysis, T classification remained the only independent factor associated with the development of SLE (P < 0.001). SLE developed
Table 1 Univariate analyses of clinicopathologic characteristics predictive of significant laryngeal edema after radiotherapy. Variable
Total, n (%)
Gender Age, years Alcohol (n = 126)c Smoking (n = 126)c Comorbidity
Second cancer BMI, kg/m2
Albumin, g/dL (n = 123)c Location Laryngeal subsite
T classification
N classification Overall stage
Differentiation (n = 108)c
Chemotherapy c
RT dose, Gy (n = 123)
Male Female 665 >65 Yes No Yes No Diabetes Cardiovascular Pulmonary Yes No <18 18–25 >25 <3.3 P3.3 Larynx Hypopharynx Glottis Supraglottis Subglottis T1 T2 T3 T4 N0 N1–3 I II III IV Well (G1) Moderate (G2) Poorly (G3) Yes No 668 >68
124 (98) 3 (2) 70 (55) 57 (45) 82 (65) 44 (35) 105 (83) 21 (17) 26 (20) 50 (39) 23 (18) 33 (26) 94 (74) 9 (7) 90 (71) 28 (22) 11 (9) 112 (91) 81 (64) 46 (36) 61 (75) 15 (19) 5 (6) 57 (45) 20 (16) 21 (17) 29 (23) 75 (59) 52 (41) 51 (40) 8 (6) 14 (11) 54 (43) 36 (33) 67 (62) 5 (5) 59 (46) 68 (54) 24 (20) 99 (80)
Abbreviations: BMI, body mass index; RT, radiotherapy. a Significant laryngeal edema was defined as grade P 2 by RTOG classification.6 b Assessed using the two-sided Fisher’s exact or v2 test. c Not known in other patients.
Laryngeal edemaa, n (%)
Pb
Grade 0–1
Grade 2–4
71 (57) 0 41 (59) 30 (53) 41 (50) 30 (68) 58 (55) 13 (62) 16 (62) 28 (56) 11 (65) 18 (55) 53 (56) 3 (33) 49 (54) 19 (68) 3 (27) 65 (58) 51 (63) 20 (43) 45 (74) 4 (27) 2 (40) 45 (79) 5 (25) 9 (43) 12 (41) 52 (69) 19 (37) 41 (80) 2 (25) 6 (43) 22 (41) 27 (75) 31 (46) 3 (60) 26 (44) 45 (66) 12 (50) 58 (59)
53 (43) 3 (100) 29 (41) 27 (47) 41 (50) 14 (32) 47 (45) 8 (38) 10 (38) 22 (44) 12 (35) 15 (45) 41 (44) 6 (67) 41 (46) 9 (32) 8 (73) 47 (42) 30 (37) 26 (57) 16 (26) 11 (73) 3 (60) 12 (21) 15 (75) 12 (57) 17 (59) 23 (31) 33 (63) 10 (20) 6 (75) 8 (57) 32 (59) 9 (25) 36 (54) 2 (40) 33 (56) 23 (34) 12 (50) 41 (41)
0.048 0.502 0.050 0.574 0.517 0.986 0.388 0.855 0.169
0.050 0.001 0.002
<0.001
<0.001 <0.001
0.025
0.012 0.446
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Table 2 Tumor recurrences in patients with and without significant laryngeal edema.
a b
Laryngeal edemaa, n (%)
Pb
Variable
N (%)
Grade 0–1
Grade 2–4
Total Sites of recurrences Primary Larynx (n = 81) Hypopharynx (n = 46) Regional Distant Total
127
71 (56)
56 (44)
20 (16) 11 (14) 9 (20) 13 (10) 4 (4) 27 (21)
3 2 1 2 0 5
17 (30) 9 (30) 8 (30) 11 (20) 4 (7) 22 (39)
(4) (2) (5) (3) (7)
<0.001 0.009 0.005 0.002 0.023 <0.001
Defined as grade P 2 by the RTOG classification of laryngeal edema.6 Assessed using the two-sided Fisher’s exact or v2 test.
Table 3 Detection of residual or recurrent tumors in patients with/without laryngeal edema. Imaging
Recurrences Yes
Local (primary sites) PET/CT (n = 113) Yes 15 (TP) No 2 (FN) CT (n = 111) Yes 13 (TP) No 6 (FN) Regional (cervical lymph nodes) PET/CT (n = 113) Yes 10 (TP) No 1 (FN) CT (n = 109) Yes 9 (TP) No 4 (FN)
Total
Table 4 Outcomes of treatments of the 27 patients with severe laryngeal edema. Variable
No
8 (FP) 88 (TN) 13 (FP) 79 (TN)
23 90 26 85
4 (FP) 98 (TN)
14 99
10 (FP) 86 (TN)
19 90
Abbreviations: PET, positron emission tomography; TP, true-positive; FP, falsepositive; FN, false-negative; TN, true-negative; PPV, positive predictive value; NPV, negative predictive value.
significantly more frequently in patients with T2–4 tumors than in those with T1 tumors (odds ratio [OR] = 5.070, 95% confidence interval [CI] = 1.999–12.857; P = 0.001). Of the 127 patients, 27 (21%) had residual or recurrent tumors, 20 at the primary tumor site, 13 at cervical nodes, and four at distant sites (Table 2). Local failure based on T stage was observed 3 of 57 T1 patients (5%), 5 of 20 T2 patients (25%), 4 of 21 T3 patients (19%), and 8 of 29 T4 patients (28%) (P = 0.026). Recurrent tumors were observed in 22 (39%) patients with and 5 (7%) without SLE (P < 0.001). The ability of imaging modalities to detect locoregional
Laryngeal edema Grade 3 Grade 4 Location Larynx Hypopharynx T classification T1–2 T3–4 N classification N0 N+ Treatments Steroid Antibiotics Tracheostomy Hyperbaric oxygen therapy Residual or recurrent tumors Local (n = 11) Regional (n = 6)
Laryngeal edema, n (%)
P
No change
Improveda
12 (60) 6 (86)
8 (40) 1 (14)
8 (67) 10 (67)
4 (33) 5 (33)
7 (70) 11 (65)
3 (30) 6 (35)
6 (60) 12 (71)
4 (40) 5 (29)
13 (62) 17 (71) 16 (80) 2 (100)
8 7 4 0
(38) (29) (20) (0)
0.323 0.250 0.023 0.436
9 (82) 5 (83)
2 (18) 1 (17)
0.226 0.378
0.224
0.660
0.561
0.439
a Defined as grade 6 2 compared with grade 3–4 laryngeal edema on RTOG classification after treatments.
disease is shown in Table 3. FDG PET/CT was performed in 113 patients and correctly evaluated 15 of the 20 patients with local recurrences and 10 of the 13 with regional recurrences (Fig. 3). CT was performed in 111 patients and correctly evaluated 13 of 20 patients with local recurrences and 9 of 13 with regional recurrences. Therefore, the overall sensitivity, specificity, accuracy, and
Figure 3 A case of true-positive PET/CT result for local recurrence. The laryngeal edema on contrast-enhanced CT (A) was correctly interpreted as local recurrence with a focal 18 F-FDG uptake on PET (B) and integrated PET/CT (C) images that was confirmed by biopsy.
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positive and negative predictive values (PPV and NPV) of PET/CT for identifying local recurrences were 88%, 92%, 91%, 65%, and 98%, respectively, while those of CT were 68%, 88%, 83%, 50%, and 83%, respectively. The overall sensitivity, specificity, accuracy, PPV and NPV of PET/CT for detecting regional recurrences were 91%, 96%, 96%, 71%, and 99%, respectively, while those of CT were 69%, 90%, 87%, 47% and 96%, respectively. The diagnostic capacity of PET/CT appeared to be higher than that of CT, but statistical differences were not calculated because each of these tests was not performed in all patients. Of 29 patients with severe SLE (grade 3 or 4), 21 were treated with intravenous or oral steroids, 24 were treated with antibiotics, 20 underwent tracheostomy, and 2 received hyperbaric oxygen therapy (Table 4). Tracheostomy was performed in 3 of 57 T1 patients (5%) and 17 of 70 T2–T4 patients (10%) (P = 0.003). We found that severe SLE improved in 9 (31%) patients but remained unchanged in 18 (62%); the other two patients did not undergo proper long-term evaluation after treatment. When we compared the clinical parameters in patients with and without improvements in severe SLE, we observed no significant differences in grades of laryngeal edema, tumor location, T and N classifications, treatment modalities, and rates of locoregional recurrence. The median follow-up time of survivors was 35 months (range, 6–74 months). The 3-year overall survival rate of all patients was 72%, 87% in the non-SLE group and 54% in the SLE group (P < 0.001). Discussion Laryngeal edema is one of the most common side effects of RT for head and neck cancer, with 15–59% of patients with head and neck cancers developing grade P 2 laryngeal edema at least once within 2 years after RT.4,7–9 Dosimetric and normal tissue complication probability (NTCP) models have indicated that laryngeal edema was correlated with mean dose to the larynx P50Gy.3,7,8 When mean laryngeal dose and volume are maintained at <43.5Gy and <27%, respectively, the incidence of laryngeal edema was minimal (<20%).3 We observed SLE in 56 of our 127 (44%) patients, which is within ranges previously reported.4,7,8 We did not detect a relationship between RT dose and laryngeal edema, since 124 (98%) of our patients received a curative RT dose to the larynx, ranging from 62Gy to 80Gy, a dose associated with RT of carcinomas arising in the larynx and hypopharynx. Similar to prior reports,4,9 we found that SLE rate was related to high primary tumor stage. Fibrotic changes following RT may lead to blockade of lymphatic vessels, causing laryngeal edema, particularly in the supraglottic areas, that may correlate with tumor burden and location.4 Lymphatic flow is greater up to the supraglottis or down to the subglottis than in the glottis. Thus, laryngeal edema is more frequently seen in supraglottic and subglottic areas. Furthermore, our univariate analysis showed that SLE incidence was higher in patients with supraglottic and subglottic cancers than in patients with glottic cancers (70% vs. 26%, P = 0.001). We found that T classification was the only factor independently predictive of SLE, with the risk of SLE being greater in patients with T2–4 than in those with T1 tumors (OR = 5.070, P = 0.001). This finding suggests the SLE may be associated with a larger tumor burden prior to RT or with tumors remaining or recurring at the primary tumor site after RT.4,9 Laryngeal edema frequently develops during or shortly after treatment and tends to regress over time.8 Patients with laryngeal edema of grade P 2 may have upper airway obstruction, with some having severe airway obstruction requiring an emergency tracheostomy. Irradiation of the larynx and pharynx with a high RT dose may result in progressive edema and associated fibrosis, leading to long-term problems with phonation and swallowing impairment.3,8 Laryngeal edema may be an early detectable morphologic
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change predicting late functional impairment.8 Persistent edema may be caused by exogenous stimulation, infection, surgical trauma, delayed RT effects, or residual or recurrent tumors.4 Antibiotics or steroids may be used to treat persistent laryngeal edema unresponsive by initial conservative treatment methods, such as discontinuing alcohol, cigarette intake, and voice rest. Hyperbaric oxygen therapy (HBO) has also been utilized to treat radiation necrosis (grade IV laryngeal edema), but its efficacy remains unclear.10,11 We found that these treatment methods contributed to improving edema and symptoms in some of our cases with severe SLE, but we could not identify any factors predictive of improvements. Early reports noted that local recurrences in about 50% of patients were related to persistent laryngeal edema.4,9,12–14 Moreover, laryngeal edema persisting for >3 months may suggest the presence of residual or recurrent tumors.14 We observed residual or recurrent local tumors in 22 of 56 (39%) patients with SLE, with the rate higher in patients who did not show improvements after treatment.4,9,12–14 Because of difficulties distinguishing tumor recurrence from post irradiation changes, frequent biopsies have been recommended to determine whether a residual or recurrent tumor is present.12,13 However, laryngeal biopsy may incite a fulminant perichondritis, leading to chondroradionecrosis, and repeated negative biopsy results cannot exclude the presence of tumors.14 Imaging methods, including CT and/or FDG PET or combined PET/CT, may differentiate between recurrent tumors and laryngeal edema.5,15–17 Recently, FDG PET/CT was shown to have greater sensitivity and specificity than CT in detecting active residual or recurrent diseases after RT or chemoradiotherapy.5,16,17 Indeed, we found that the NPV of FDG PET/CT for detecting viable tumors in the larynx or hypopharynx was as high as 98%, suggesting that repeated biopsies in patients with PET-negative lesions are not necessary. It may be necessary, however, to confirm tumor recurrences in patients with PET-positive lesions in the surrounding laryngeal edema because tumor recurrence rates were higher and survival rates were lower in patients with than without SLE. Our study has the potential limitations of a retrospective study. This may affect the real incidence and outcomes of patients with laryngeal edema and the diagnostic values of imaging modalities. Because all included patients had primary tumors of the larynx or hypopharynx, we could not assess the effects of RT on the uninvolved larynx. In addition, while some lesions interpreted as positive on imaging were histologically confirmed, others were assessed only by imaging workup and/or follow-up imaging. The latter may be useful in oncological practice because not all patients suspected of having recurrent tumors are able to undergo biopsy procedures for pathologic confirmation. In conclusion, we found that a significant proportion of patients with laryngeal or hypopharyngeal carcinomas had SLE after definitive RT. Patients with T2–4 tumors were at a higher risk of SLE than other patients. SLE is frequently associated with residual or recurrent tumors and subsequent low patient survival rates. These patients should be carefully monitored for airway problems, as well as for tumor recurrences, which may be differentially diagnosed from laryngeal edema without viable tumors using FDG PET/CT. Conflict of interest statement None declared. References 1. Fung K, Yoo J, Leeper HA, Hawkins S, Heeneman H, Doyle PC, et al. Vocal function following radiation for non-laryngeal versus laryngeal tumors of the head and neck. Laryngoscope 2001;111:1920–4. 2. Patterson JM, Hildreth A, Wilson JA. Measuring edema in irradiated head and neck cancer patients. Ann Otol Rhinol Laryngol 2007;116:559–64.
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