Impact of total lesion glycolysis measured by 18F-FDG-PET/CT on overall survival and distant metastasis in hypopharyngeal cancer
- Authors:
- Published online on: June 23, 2016 https://doi.org/10.3892/ol.2016.4765
- Pages: 1493-1500
Abstract
Introduction
Positron emission tomography/computed tomography (PET/CT) using 18F-2-fluorodeoxyglugose (18F-FDG) is a widely used and accurate imaging method for the staging of various cancers (1–3). The semiquantitative measurement of the maximum or mean 18F-FDG-uptake, which is assessed using 18F-FDG-PET/CT, is usually obtained according to maximum standardized uptake value (SUVmax) or mean SUV (SUVmean) (1,4–14). A high SUVmax in a primary tumor is associated with a shorter overall survival (OS) time in hypopharyngeal squamous cell carcinoma (HPSCC) and other cancers (1,4–11). Recently, it has become possible to quantitatively calculate volume-based 18F-FDG-uptake parameters, including metabolic tumor volume (MTV), total lesion glycolysis (TLG) and peak SUV (SUVpeak), following the development of software programs (4–7,12–16). Previous studies have suggested that MTV and/or TLG can predict the 2- to 4-year OS rates in several cancers (4–7,12,13,15,16). Roh et al (16) reported that in HPSCC patients who underwent radical radiotherapy, MTV and TLG are significantly associated with OS time, although volume-based 18F-FDG-uptake parameters have not thus far been investigated in any HPSCC patients who underwent radical treatment, including surgery and radiotherapy. Moreover, the association between 18F-FDG-uptake parameters and clinicopathological parameters in HPSCC has not been fully investigated.
Tumor thickness, depth of invasion and pathological tumor volume are pathologically considered to be quantitative values and prognostic parameters in various cancers, including HPSCC (2,8,17–19). In previous studies, tumor thickness has been defined as the distance from the surface to the deepest portion of invasion, while depth of invasion has been defined as the distance from a theoretically reconstructed normal mucosal line to the deepest portion of invasion (8,17). Pathological tumor volume is calculated by three-dimensional measurements (14,18).
Distant metastasis (DM) is clinically associated with a poor prognosis in a number of cancer types (5,6,20–24). The incidence rate of DM following initial treatment in HPSCC ranges from 10–30%, and DM generally occurs within 3 years (22,23). Furthermore, the majority of patients with DM of HPSCC succumb within 1 year of diagnosis, and DM directly affects the 3-year OS rate in HPSCC (20,22,23). Recently, higher TLG was reported to be associated with a shorter DM-free survival (DMFS) time in oral SCC (OSCC) and oropharyngeal SCC (OPSCC) (5,6). However, to the best of our knowledge, the association between TLG and DMFS in HPSCC has not been previously assessed.
In the present study, the possible correlation between 18F-FDG-uptake parameters and OS was investigated in patients with HPSCC, and the possible association between DMFS and 18F-FDG-uptake parameters was assessed. Furthermore, the correlations between 18F-FDG-uptake parameters and clinicopathological parameters was also investigated in HPSCC.
Patients and methods
Patients
Between June 2008 and December 2011, 54 patients, who were newly diagnosed with HPSCC by pathological examination Aichi Cancer Center Hospital (Nagoya, Japan), underwent pretreatment 18F-FDG-PET/CT. Prior to treatment, 1 patient with DM was excluded. Therefore, 53 patients who received radical treatment were enrolled in this study, which was approved by the Institutional Review Board at Aichi Cancer Center Hospital. All patients provided informed consent for all treatments and examinations. Clinical staging was decided by routine physical examination, nasopharyngoscopy, chest radiography, enhanced cervical computed tomography (CT) or magnetic response imaging, and 18F-FDG-PET/CT. 18F-FDG-PET/CT was not used for the classification of either T or N stage, and tumor-node-metastasis was classified based on the International Union Against Cancer (sixth edition) (25).
Treatment
In accordance with our previous study and another study (9,12), the 53 patients were grouped by primary tumor treatment modality as follows: Curative surgery plus radiation therapy (RT) with or without chemotherapy (surgery group; n=19) and radical RT plus chemotherapy (RT group; n=34). The selection of primary treatment modality, but not 18F-FDG-PET/CT, depended on whether patients wished for larynx preservation. In total, 34 patients in the RT group were treated with radical RT at a total dose of 60–70 Gy, with 1.8–2 Gy per fraction; all other RT procedures were used as previously described (26). In the RT group, 8 patients underwent neck dissection, while 2 patients were treated with RT alone due to a poor general condition. Following completion of treatment, an effort was made to identify those with early locoregional recurrence (LR) at an outpatient clinic, and salvage therapy was performed. The clinical characteristics of all patients are shown in Table I.
Pathological parameters
Pathological measurements could be taken of 6 primary tumors that underwent surgery without preoperative chemotherapy, and 1 tumor that was not detected on 18F-FDG-PET/CT (T1 HPSCC) was excluded. Therefore, a total of 5 lesions were measured using sections stained with hematoxylin and eosin. Tumor thickness and depth of invasion were measured by a pathologist using a microscope (LV-100ND; Nikon, Tokyo, Japan) with an accuracy of 0.1 mm, according to our previous study (8). Based on the study by Murphy et al (14), the pathological tumor volume was calculated using the following formula: Pathological tumor volume = π/6 × (xpath × ypath × zpath), where xpath, ypath and zpat are the three orthogonal diameters obtained from the tumor specimen resected from the primary tumor site.
18F-FDG-PET/CT
All patients were scanned using a FDG-PET/CT machine (Biograph TruePoint PET/CT/40 with TrueV; Siemens Healthcare Medical Solutions Inc., Malvern, PA, USA). The interval between 18F-FDG-PET/CT and the start of therapy was 18.6±10.3 days [mean ± standard deviation (SD)], and the blood glucose level at the time of injection of 18F-FDG was 104.9±15.5 mg/dl (mean ± SD). Patients fasted for 6 h prior to an intravenous infusion of 185–370 MBq 18F-FDG, depending on bodyweight, and images were acquired 90 min after intravenous administration of the tracer. Low-dose CT images were used for attenuation correction of the PET data. The CT dose for RANDO Phantom (Alderson Research Laboratories Inc., Long Island, NY, USA) was 4.3 mSv. PET images were reconstructed using a Gaussian filter of 4.0 mm full width at half maximum value. All image reconstructions were performed with the ordered subset expectation maximization algorithm, incorporating a CT-based transmission map. All other PET/CT procedures were published previously (3).
18F-FDG-uptake parameter
A focus was considered to be positive if its activity was significantly above that of the expected background, and the boundaries were automatically drawn to include the primary tumor within the hypopharynx by a click on each axial, coronal and sagittal 18F-FDG-PET/CT image. The 3-dimensional images were created in SUV mode for semiquantitative evaluation on a workstation (Advantage Workstation 4.6 software program PET VCAR; GE Healthcare, Chalfont, UK). The level of 18F-FDG-uptake was automatically calculated as the SUV according to the following formula: SUV = tissue concentration (Bq/g) / [injection dose (Bq) / body weight (g)]. Applying the findings of our previous study (9), the SUVmax of the primary hypopharyngeal tumor was automatically obtained from a volumetric region of interest designated as a site of abnormal accumulation on several consequent 3-dimensional images. SUVpeak was determined according to the average SUV within a 1 cm3 spherical volume of interest (VOI) that included the maximum pixel. In accordance with the study by Abd El-Hafez et al (5), with a minor modification, the MTV and SUVmean of the VOIs were calculated by adopting a fixed threshold fraction of the SUVmax in the primary tumor. The threshold was 45% of the SUVmax based on Phantom analyses. TLG was calculated according to the following formula: TLG = SUVmean × MTV. A representative 18F-FDG-PET/CT image is presented as an example in Fig. 1.
Statistical analysis
Statistical analysis was performed using the JMP program (version 9; SAS, Cary, NC, USA). Differences in clinical T classification between two groups, which were detectable or undetectable on 18F-FDG PET/CT, were assessed using Fisher's exact test.
Among the 50 patients with a primary tumor detected on 18F-FDG-PET/CT, correlations between 18F-FDG-uptake parameters were analyzed using simple regression analysis, and the associations between clinical parameters (age, gender, T and N classification, clinical stage, tumor site and treatment group) and 18F-FDG-uptake parameters (SUVmax, SUVpeak, MTV and TLG) were analyzed using Spearman's rank correlation and the Mann-Whitney U-test. Among 5 patients, associations between 18F-FDG-uptake parameters and pathological parameters (tumor thickness, depth of invasion and pathological tumor volume) were estimated by simple regression analysis.
In all cases, the survival time was defined as the period from 18F-FDG-PET/CT to the target event or last contact. The target events included mortality for OS, LR for LR-free survival (LRFS) and DM for DMFS. Applying a previously described method (8,9), the Kaplan-Meier technique was used to estimate OS, LRFS and DMFS curves, and various 18F-FDG-uptake cutoff values were tested using log-rank test in OS analysis. All patients could be divided into two groups based on SUVmax (SUVmax ≥28.5; SUVmax <28.5), SUVpeak (SUVpeak ≥19; SUVpeak <19), MTV (MTV ≥12; MTV <12) and TLG (TLG ≥42; TLG <42). In the multivariate analysis, a Cox proportional hazards model was used. The small number events in the dataset limited the number of parameters that could be analyzed in the multivariate model. In accordance with the study by Lim et al (6), the T classification is a strong prognostic parameter and may provide a degree of the same information as the 18F-FDG-uptake parameters of the primary tumor. Moreover, our previous study and other studies have reported that clinical T4 category is significantly associated with high-risk DM compared with clinical T1-3 category (20,21). In the multivariate analysis with adjustment for clinical T category (clinical T1-3/clinical T4) and treatment group (surgery/RT), the present study analyzed whether any of the 18F-FDG-uptake parameters were correlated with OS or DMFS. P<0.05 was considered to indicate a statistically significant difference.
Results
18F-FDG-uptake of the primary tumor
The sensitivity of detection of the hypopharyngeal site on 18F-FDG PET/CT was 94.3% (50/53). All false-negative cases, which were undetectable by 18F-FDG PET/CT, were T1 HPSCC. Tumors with T2-T4 classification were detected more frequently than those with T1 classification (P<0.01).
18F-FDG-uptake and clinical parameters
Among the 50 patients with a primary tumor detected on 18F-FDG PET/CT, the SUVmax, SUVpeak, MTV and TLG values (mean ± SD) of the primary tumor were 22.3±10.5 g/ml, 14.5±7.0 g/ml, 5.1±5.5 cm3 and 73.7±88.8 g, respectively. SUVmax was significantly correlated with SUVpeak (P<0.01), while TLG was correlated with SUVmax (P<0.01), SUVpeak (P<0.01) and MTV (P<0.01), as shown in Fig. 2. The associations between the clinical parameters and the 18F-FDG-uptake parameters are shown in Table II. Clinical T classification was significantly correlated with all 18F-FDG-uptake parameters (P<0.01), while clinical stage was correlated with SUVmax (P<0.05), SUVpeak (P<0.02) and TLG (P<0.02). The surgery group exhibited significantly greater MTV (P<0.01) and TLG (P<0.02) values.
18F-FDG-uptake and pathological parameters
TLG was significantly correlated with tumor thickness (P<0.01) and depth of invasion (P<0.03), and MTV was correlated with pathological tumor volume (P<0.02), as shown in Fig. 3.
Clinical course
At the end of the study, the mean ± SD follow-up periods among all patients, the 39 patients who remained alive (73.6%) and the 14 patients who had succumbed (26.4%) was 33.5±13.8, 37.7±12.7 and 21.6±8.8 months, respectively. A total of 13 patients (24.5%) succumbed to HPSCC. In total, 16 (30.2%) exhibited LR. Of these 16 patients, 11 underwent radical surgery. Overall, 12 patients (22.6%) exhibited DM (lung, n=9; mediastinum, n=1; lung and mediastinum, n=1; and hip, n=1), and the mean ± SD period between 18F-FDG-PET/CT and DM was 12.0±4.9 months. Among all the patients, the 3-year OS, LRFS and DMFS rates were 72.7, 71.5 and 76.4%, respectively. In total, 15 patients (28.3%), who were diagnosed with second primary cancer received radical treatment.
Univariate survival analysis
Applying the method described previously (8,9), various 18F-FDG uptake parameter cutoff values were tested using the log-rank test in OS analysis. The cutoff values with the lowest P-values were used in these analyses: SUVmax=28.5, SUVpeak=19, MTV=12 and TLG=42. It was found that SUVmax ≥28.5 (P<0.04), SUVpeak ≥19 (P<0.05), MTV ≥12 (P<0.03) and TLG ≥42 (P<0.01) could significantly differentiate the shorter survival group. Univariate analyses of OS, LRFS and DMFS are shown in Table III. MTV ≥12 (P<0.03) and TLG ≥42 (P<0.01) were significantly correlated with poorer DMFS.
Multivariate survival analysis
Upon multivariate analysis with adjustment for clinical T category (clinical T1-3/clinical T4) and treatment group (surgery/RT), the patients with SUVmax ≥28.5 exhibited significantly poorer OS (P<0.03), and TLG ≥42 was significantly correlated with shorter OS (P<0.03) and DMFS (P<0.01) times. Multivariate analysis of OS and DMFS are shown in Table IV. Kaplan-Meier curves for OS (SUVmax ≥28.5 and SUVmax <28.5), and OS and DMFS (TLG ≥42 and TLG <42) are shown in Fig. 4. In the multiple survival analysis with adjustment for clinical T category (clinical T1-3/T4) and treatment group (surgery/RT), FDG-uptake parameters were not significantly assocaited with LRFS (SUVmax ≥28.5: Hazard ratio (HR), 1.88, 95% confidence interval (CI), 0.51–12.1, P=0.38; SUVpeak ≥19: HR, 1.92, 95% CI, 0.53–12.3, P=0.35; MTV≥12: HR, 1.27, 95% CI, 0.14–27.4, P=0.84; TLG≥12: HR, 1.14, 95% CI, 0.37–3.33, P=0.81).
Discussion
18F-FDG-PET/CT is an important imaging procedure for the staging of numerous cancers, although its full potential has yet to be established (1–4,8,9). SUVmax is a single-voxel representation of the maximum 18F-FDG uptake (4). A number of studies have investigated the close correlation between SUVmax and OS (1,4–11). In our previous studies, high SUVmax was associated with a shorter OS time and a greater tumor thickness in OSCC, and with a poorer OS in HPSCC (8,9). Although several studies have reported no significant association between SUVmax and OS (12,13), two recent meta-analyses and a review of HNSCC have demonstrated that that an increased SUVmax indicates poorer OS (8,10,11). The present results demonstrating a significant association between SUVmax ≥28.5 and a poorer OS is in agreement with these previous studies (1,4–11).
SUVpeak is a hybrid SUV measurement that includes the local average SUV value in a group of voxels surrounding the voxel with the highest activity (4). A higher SUVpeak was shown to be associated with a shorter OS in non-small lung cancer (15). To the best of our knowledge, the present study found, for the first time, that a higher SUVpeak is significantly correlated with a shorter OS time in HPSCC.
MTV functions as a volumetric and metabolic biomarker, and can be used to estimate the tumor volume based on the distribution of metabolic activity (4). Murphy et al (14) reported that MTV in 23 OSCC patients was associated with pathological tumor volumes, and Burri et al (19) reported that MTV in OSCC was associated with pathological tumor volume according to linear regression analysis. The present result demonstrating a significant association between MTV and pathological tumor volume is in agreement with these studies (14,19). Furthermore, previous studies have demonstrated that a high MTV of the primary tumor is significantly associated with a shorter OS time in HPSCC patients who underwent radical radiotherapy, as well as in other cancer types, and the present result demonstrating a significant correlation between MTV ≥12 and a shorter OS time is in agreement with these studies (4–7,12,13,16).
TLG, which incorporates MTV and SUVmean, theoretically represents the total activity of all metabolically active cancer cells (4). In HPSCC patients who underwent radical radiotherapy, as well as in other cancer types, a high TLG value has been demonstrated to be significantly associated with a shorter OS time, and the present result demonstrating a significant association between TLG ≥42 and a shorter OS time is in agreement with these studies (4–7,12,13,16).
It has been demonstrated that high TLG of the primary tumor is associated with a shorter DMFS time and a higher incidence of DM (13). TLG has been shown to predict DMFS in 19 patients with head and neck cancer (13), and high TLG has also been associated with a shorter OS time and a higher incidence of DM in OSCC (5). Additionally, TLG has been shown to be associated with OS and DMFS in OPSCC (6). However, no associations have been reported between TLG and DMFS in HPSCC patients to date.
In a previous study of 595 HPSCC patients, the median time from the last treatment to DM was 11.5 months, and 95% of the DM occurred prior to 36 months (23). Moreover, in a recent review of HPSCC, the number of patients who developed DM was stated to range between 10 and 30%, and the median survival time was typically <1 year (22). These studies show that the development of DM in HPSCC directly affects the 3-year OS rate (22–24). We hypothesized that 18F-FDG-uptake parameters are associated with DMFS, as the presence of DM affects 3-year OS rates. In the present study, TLG was associated with the 3-year OS and DMFS rates. Based on the present results and those of other studies, it is likely that pretreatment 18F-FDG-PET/CT provides non-invasive and effective information for identifying the patients at high-risk of DM (5,6,13).
A limitation of the present study is the relatively small number of subjects, and in the future, an analysis of larger numbers of patients will be required.
In conclusion, to the best of our knowledge, the present study demonstrated for the first time that high TLG was significantly correlated with shorter OS and DMFS times in HPSCC patients who underwent radical treatment, including surgery and radiotherapy. Pretreatment 18F-FDG-PET/CT is thus likely to provide valuable prognostic parameters for identifying groups of HPSCC patients with shorter OS and DMFS times.
Acknowledgements
The authors are grateful to the technical staff for the PET/CT operation. The present study was supported by the Japan Society for the Promotion of Science Grants-in-Aid for Science Research (grant nos. 2479821 and 16K11253).
References
|
Kato H, Kuwano H, Nakajima M, Miyazaki T, Yoshikawa M, Ojima H, Tsukada K, Oriuchi N, Inoue T and Endo K: Comparison between positron emission tomography and computed tomography in the use of the assessment of esophageal carcinoma. Cancer. 94:921–928. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Daisne JF, Duprez T, Weynand B, Lonneux M, Hamoir M, Reychler H and Grégoire V: Tumor volume in pharyngolaryngeal squamous cell carcinoma: Comparison at CT, MR imaging and FDG PET and validation with surgical specimen. Radiology. 223:93–100. 2004. View Article : Google Scholar | |
|
Ozawa Y, Hara M, Shibamoto Y, Tamaki T, Nishio M and Omi K: Utility of high-definition FDG-PET image reconstruction for lung cancer staging. Acta Radiol. 54:916–920. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Paidpally V, Chirindel A, Lam S, Agrawal N, Quon H and Subramaniam RM: FDG-PET/CT imaging biomarkers in head and neck squamous cell carcinoma. Imaging Med. 4:633–647. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
El-Hafez Abd YG, Moustafa HM, Khalil HF, Liao CT and Yen TC: Total lesion glycolysis: A possible new prognostic parameter in oral cavity squamous cell carcinoma. Oral Oncol. 49:261–268. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Lim R, Eaton A, Lee NY, Setton J, Ohri N, Rao S, Wong R, Fury M and Schöder H: 18F-FDG PET/CT metabolic tumor volume and total lesion glycolysis predict outcome in oropharyngeal squamous cell carcinoma. J Nucl Med. 53:1506–1513. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Moon SH, Choi JY, Lee HJ, Son YI, Baek CH, Ahn YC, Park K, Lee KH and Kim BT: Prognostic value of 18F-FDG PET/CT in patients with squamous cell carcinoma of the tonsil: Comparisons of volume-based metabolic parameters. Head Neck. 35:15–22. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Suzuki H, Fukuyama R, Hasegawa Y, Tamaki T, Nishio M, Nakashima T and Tatematsu M: Tumor thickness, depth of invasion and Bcl-2 expression are correlated with FDG-uptake in oral squamous cell carcinomas. Oral Oncol. 45:891–897. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Suzuki H, Kato K, Fujimoto Y, Itoh Y, Hiramatsu M, Maruo T, Naganawa S, Hasegawa Y and Nakashima T: 18F-FDG-PET/CT predicts survival in hypopharyngeal squamous cell carcinoma. Ann Nucl Med. 27:297–302. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Xie P, Li M, Zhao H, Sun X, Fu Z and Yu J: 18F-FDG PET or PET/CT to evaluate prognosis for head and neck cancer: A meta-analysis. J Cancer Res Clin Oncol. 137:1085–1093. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang B, Li X and Lu X: Standardized uptake value is of prognostic value for outcome in head and neck squamous cell carcinoma. Acta Otolaryngol. 130:756–762. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Park GC, Kim JS, Roh JL, Choi SH, Nam SY and Kim SY: Prognostic value of metabolic tumor volume measured by 18F-FDG-PET/CT in advanced -stage squamous cell carcinoma of larynx and hypopharynx. Ann Oncol. 24:208–214. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Picchio M, Kirienko M, Mapelli P, Dell'Oca I, Villa E, Gallivanone F, Gianolli L, Messa C and Castiglioni I: Predictive value of pre-therapy (18)F-FDG-PET/CT for the outcome of (18)F-FDG-PET-guided radiotherapy in patients with head and neck cancer. Eur J Nucl Med Mol Imaging. 41:21–31. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Murphy JD, Chisholm KM, Daly ME, Wiegner EA, Truong D, Iagaru A, Maxim PG, Loo BW Jr, Graves EE, Kaplan MJ, et al: Correlation between metabolic tumor volume and pathologic tumor volume in squamous cell carcinoma of the oral cavity. Radiother Oncol. 101:356–361. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Machtay M, Duan F, Siegel BA, Snyder BS, Gorelick JJ, Reddin JS, Munden R, Johnson DW, Wilf LH, DeNittis A, et al: Prediction of survival by [18F] fluorodeoxyglucose positron emission tomography in patients with locally advanced non-small-cell lung cancer undergoing definitive chemoradiation therapy: Results of the ACRIN 6668/RTOG 0235 trial. J Clin Oncol. 31:3823–3830. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Roh JL, Kim JS, Kang BC, Cho KJ, Lee SW, Kim SB, Choi SH, Nam SY and Kim SY: Clinical significance of pretreatment metabolic tumor volume and total lesion glycolysis in hypopharyngeal squamous cell carcinomas. J Surg Oncol. 110:869–875. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Pentenero M, Gandolfo S and Carrozzo M: Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: A review of the literature. Head Neck. 27:1080–1091. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Tomifuji M, Imanishi Y, Araki K, Yamashita T, Yamamoto S, Kameyama A and Shiotani A: Tumor depth as a predictor of lymph node metastasis of supraglottic and hypopharyngeal cancers. Ann Surg Oncol. 18:490–496. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Burri RJ, Rangaswamy B, Kostakoglu L, Hoch B, Genden EM, Som PM and Kao J: Correlation of positron emission tomography standard uptake value and pathologic specimen size in cancer of the head and neck. Int J Radiat Oncol Biol Phys. 71:682–688. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Spector JG, Sessions DG, Haughey BH, Chao KS, Simpson J, El Mofty S and Perez CA: Delayed regional metastases, distant metastases and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx. Laryngoscope. 111:1079–1087. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Shintani S, Matsuura H, Hasegawa Y, Nakayama B and Hasegawa H: Regional lymph node involvement affects the incidence of distant metastasis in tongue squamous cell carcinomas. Anticancer Res. 15:1573–1576. 1995.PubMed/NCBI | |
|
Takes RP, Strojan P, Silver CE, Bradley PJ, Haigentz M Jr, Wolf GT, Shaha AR, Hartl DM, Olofsson J, Langendijk JA, et al: Current trends in initial management of hypopharyngeal cancer: The declining use of open surgery. Head Neck. 34:270–281. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Hall SF, Groome PA, Irish J and O'Sullivan B: The natural history of patients with squamous cell carcinoma of the hypopharynx. Laryngoscope. 118:1362–1371. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Hauswald H, Simon C, Hecht S, Debus J and Lindel K: Long-term outcome and patterns of failure in patients with advanced head and neck cancer. Radiat Oncol. 6:702011. View Article : Google Scholar : PubMed/NCBI | |
|
Sobins LH and Wittekind C: TNM Classification of Malignant Tumours (6th). Wiley and Sons. New York, NY: 2002. | |
|
Nakahara R, Kodaira T, Furutani K, Tachibana H, Tomita N, Inokuchi H, Mizoguchi N, Goto Y, Ito Y and Naganawa S: Treatment outcomes of definitive chemoradiotherapy for patients with hypopharyngeal cancer. J Radiat Res. 53:906–915. 2012. View Article : Google Scholar : PubMed/NCBI |
