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ORIGINAL ARTICLE
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Impact of primary tumor size, standardized uptake values of primary tumor, and the most avid neck node on baseline 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography upon disease recurrence in head-and-neck oropharyngeal squamous cell carcinoma using standardized imaging protocol


1 Department of Radiology, The Aga Khan University Hospital, Karachi, Pakistan
2 Dow Medical College, Dow University Health Sciences, Karachi, Pakistan
3 Department of Medicine, Kings County Hospital/SUNY Downstate Hospital, New York, USA
4 Radiation Oncology, The Aga Khan University Hospital, Karachi, Pakistan

Date of Submission01-Jan-2021
Date of Acceptance22-Apr-2021
Date of Web Publication12-Jan-2022

Correspondence Address:
Maseeh uz Zaman,
Department of Radiology, The Aga Khan University Hospital, Karachi
Pakistan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/wjnm.wjnm_1_21

   Abstract 

The purpose of this prospective study was to find the impact of primary tumor size (Ts), standardized uptake values (SUVmax) of primary tumor, and the most avid neck node on disease recurrence in patients with head-and-neck (HN) oropharyngeal squamous cell carcinoma (HNOP-SCC). We included patients with HNOP-SCC (without distant metastasis – M0 disease) who had pre- and post-treatment 18-fluoro-2-deoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) using strict standardized imaging protocol from 2017 to 2019. Based on follow-up 18FDG PET/CT findings patients were categorized as disease free (no or minimal 18FDG uptake ≤ background over surgical bed and no distant metastasis) and disease recurrence (18FDG uptake > background over surgical bed with or without nodal and/or distant metastasis). Ts and SUVmax of primary tumor and the most avid neck node were compared and impact of these was studied upon disease recurrence. A total of 112 patients were included. No significant difference was seen in mean age (overall: 60 ± 14 year), gender distribution (overall M: F: 69:31%), body mass index (overall: 25.20 ± 5.82), and history of diabetes (overall: 19%) between disease free and disease recurrence groups. Similarly, no significant difference was observed for fasting blood sugar (overall: 110 ± 28 mg%), 18FDG dose (overall: 169 ± 37 MBq) and uptake period (overall: 70 ± 12 min) between two groups ensuring strict adherence to standardized imaging protocol. Significant difference (P < 0.05) was observed between disease free and disease recurrence for Ts (25 ± 10 mm vs. 33 ± 14 mm), SUVmax of primary tumor (6.2 ± 6.8 vs. 9.3 ± 7.2) and the most avid neck node (2.1 ± 3.3 vs. 4.7 ± 5.9) and median follow-up (13 ± 12 vs. 08 ± 13 months), respectively. Using receiver operating characteristic analysis, Ts >29 mm, baseline tumor SUVmax >4.6 and nodal SUVmax >6.2 were found independent predictors for disease recurrence. Nodal SUVmax >6.2 was found an independent predictor of shortest DFS than Ts and tumor SUVmax. We conclude that, in HNOP-SCC, primary Ts (>29 mm), SUVmax of primary tumor (>4.6), and the most avid neck node (>6.2) in baseline 18FDG PET/CT using standardized imaging protocol are the independent predictors of disease recurrence. Furthermore, SUVmax >6.2 of the most avid node predicts the shortest DFS than primary Ts and SUVmax of primary tumor.

Keywords: 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography, disease free survival, disease recurrence, head and neck cancer, primary tumor size, squamous cell cancer, standardized uptake values



How to cite this URL:
Fatima N, Zaman A, Zaman U, Zaman S, Tahseen R, Zaman Mu. Impact of primary tumor size, standardized uptake values of primary tumor, and the most avid neck node on baseline 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography upon disease recurrence in head-and-neck oropharyngeal squamous cell carcinoma using standardized imaging protocol. World J Nucl Med [Epub ahead of print] [cited 2022 Jun 27]. Available from: http://www.wjnm.org/preprintarticle.asp?id=335713


   Introduction Top


Globally, head and neck (HN) cancer accounts for more than 650,000 cases, 330,000 deaths annually and constitutes 3% and 4% of total cancer incidence in the United States and Europe, respectively.[1] The most common histological type is squamous cell carcinoma (SCC) which accounts for 95% of cases (HN-SCC) and overall 5-year survival for all stages is approximately 60%.[2] Various prognostic markers indicating a dismal outcome include larger primary tumor size (Ts), greater tumor volume, higher histological grade, the presence of nodal metastasis, negative human papilloma virus (HPV), and p-16 status.[3] 18-fluoro-2-deoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) is an established modality for initial staging and restaging after treatment with higher diagnostic accuracy. Gathered data suggest that 18FDG PET/CT may serve as a noninvasive method that can indirectly measure the expression of various biologic markers of tumor aggressiveness.[4] In many HN-SCC studies, various 18FDG PET/CT metabolic markers (such as standardized uptake value [SUV] of primary tumor and nodes, metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) and morphological parameters (likely primary; Ts and volume) have been identified as valuable imaging markers to assess treatment response and long-term survival.[5],[6]

The purpose of this prospective study was to find the impact of primary Ts, (SUVmax) of primary tumor, and the most avid neck node upon disease recurrence in patients with HN oropharyngeal SCC (HNOP-SCC).


   Materials and Methods Top


This prospective study was conducted at PET/CT Section of Department of Radiology, Aga Khan University Hospital Karachi, Pakistan, from January 2017 to December 2019. Study was duly approved by ethical review committee (l2020-5555-14933). We included patients with biopsy proven oropharyngeal HN SCC (HNOP-SCC) who were referred for 18FDG PET/CT studies at baseline and follow-up for suspected recurrence. Based on baseline 18FDG PET/CT studies, patient without distant metastases (M0) were enrolled. All patients had undergone surgery, local radiation therapy, and chemotherapy (some had neoadjuvant as well). Patients with primary other than oropharynx, non-SCC or distant metastasis (M1) at presentation were excluded. We strictly followed a standardized imaging protocol for 18FDG PET/CT as per European Association of Nuclear Medicine (EANM) guidelines for both studies.[7] Based on follow-up 18FDG PET/CT findings, patients were categorized as disease free (no or minimal 18FDG uptake ≤ background over surgical bed and no distant metastasis) and disease recurrence (18FDG uptake > background over surgical bed with or without nodal and/ or distant metastasis). Ts and SUVmax of primary tumor and the most avid neck node were compared, and impact of these was studied upon disease recurrence.

18-fluoro-2-deoxyglucose positron emission tomography computed tomography imaging

18FDG PET/CT was performed as per institutional protocol adopted from EANM guidelines.[7] All patients had 4–6 h fasting (only plain water was allowed) and a fasting blood sugar <200 mg% before receiving an intravenous 18FDG dose of 3 MBq/Kg in the uptake room. During uptake period (55–75 min), patients were requested to lie comfortably and allowed to take about 500–1000 ml of plain water. Bladder was emptied before call the patient for PET/CT imaging suite equipped with Celesteion, Toshiba, Japan. A low-dose CT examination (mid brain to mid-thigh) followed by acquisition of PET imaging using 3 min/bed position from mid-thigh to head in all patients. Follow-up scans were performed with same protocols, keeping 18FDG dose, uptake time and hepatic SUVmean of baseline, and follow-up studies within ± 10%, ± 15%, and 20% min, respectively, as per published recommendations.[8] On follow-up scan, disease-free status was defined as no or minimal 18FDG uptake ≤ background over surgical bed and no distant metastasis. While disease recurrence was defined as 18FDG uptake > background over surgical bed with or without nodal and distant metastasis.

Statistical analysis

Comparisons between patient groups were performed using student's t-test for continuous variables and the Chi-square test for categorical variables. Continuous variables were described by mean ± standard deviation. Receiver operating characteristic (ROC) analysis was performed to calculate the area under the curve, and cutoff values for highest SUVmax of primary tumor, SUVmax of neck node, and primary Ts with a corresponding 95% confidence interval were estimated as predictor for tumor recurrence. Kaplan–Meier survival curve was plotted for recurrence-free survival. Statistical significance was defined as P < 0.05. Commercially available packages Microsoft excel 2010, Medcalc® and Statistical Package for the Social Sciences (SPSS-219®, IBM, USA) were used.


   Results Top


During study period, 112 patients with biopsy-proven HNOP-SCC without distant metastasis (M0) were included. No significant difference was seen in mean age (overall: 60 ± 14 year), gender distribution (overall M; F: 69:31%), body mass index (overall: 25.20 ± 5.82), and history of diabetes (overall: 19%) between disease free and disease recurrence groups [Table 1]. Similarly, no significant difference was observed for fasting blood sugar (overall: 110 ± 28 mg%), 18FDG dose (overall: 169 ± 37 MBq) and uptake period (overall: 70 ± 12 min) between two groups ensuring strict adherence to standardized imaging protocol [Table 1]. Significant difference (P < 0.05) was observed between disease free and disease recurrence for Ts (25 ± 10 mm vs. 33 ± 14 mm), SUVmax of primary tumor (6.2 ± 6.8 vs. 9.3 ± 7.2), and the most avid neck node (2.1 ± 3.3 vs. 4.7 ± 5.9) and median follow-up (13 ± 12 vs. 08 ± 13 months), respectively [Table 1]. Using ROC analysis, Ts >29 mm [95% confidence interval (CI): 0.529–0.715; [Figure 1]], baseline tumor SUVmax >4.6 [95% CI: 0.502–0.690; [Figure 2]], and nodal SUVmax >6.2 [95% CI: 0.531–0.717; [Figure 3]] were found independent predictors for disease recurrence [Figure 4]. The Kaplan–Meier survival plots for time of recurrence (or disease-free survival; DFS) revealed an overall mean DFS of 24.6 months (95% CI: 16.2–33.0; P < 0.05). The Kaplan–Meier survival plots for Ts >29 mm had a mean DFS of 17.5 month versus 21.5 month for Ts ≤29 mm [Logrank test value = 12.79; P < 0.0003; [Figure 5]]. The Kaplan–Meier survival plots for primary tumor SUVmax >4.6 had a mean DFS of 21.8 month versus 23.6 month for SUVmax ≤4.6 [Logrank test value = 6.01; P < 0.0014; [Figure 6]]. The Kaplan–Meier survival plots for most avid node SUVmax >6.2 had a mean DFS of 8.6 month versus 31.4 month for SUVmax ≤6.2 ([Logrank test value = 12.75; P < 0.0004; [Figure 7]]. Importantly SUVmax of the most avid node at baseline 18FDG PET/CT was found an independent predictor of the shortest DFS than Ts and SUVmax of primary tumor.
Table 1: Demographic comparison of head and neck cancer patients labeled as responders and non-responders on metabolic response in their follow up positron emission tomography/computed tomography studies

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Figure 1: Receiveroperatingcharacteristicanalysisofprimarytumorsize(inmm)onbaseline18FDGPET/CTaspredictorfordiseasefreeanddiseaserecurrenceonmetabolicresponseinSCCofheadandneckinfollowupstudies.AUC=AreaUnderCurve;SE=StandardError;SUV=StandardizedUptakeValue;CI=ConfidenceInterval

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Figure 2: ReceiveroperatingcharacteristicanalysisofhighestSUVmaxofprimarytumoronbaseline18FDGPET/CTaspredictorfordiseasefreeanddiseaserecurrenceonmetabolicresponseinSCCofheadandneckinfollowupstudies.AUC=AreaUnderCurve;SE=StandardError;SUV=StandardizedUptakeValue;CI=ConfidenceInterval

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Figure 3: ReceiveroperatingcharacteristicanalysisofsizeofSUVmaxofthemostavidnodeonbaseline18FDGPET/CTaspredictorfordiseasefreeanddiseaserecurrenceonmetabolicresponseinSCCofheadandneckinfollowupstudies.AUC=AreaUnderCurve;SE=StandardError;SUV=StandardizedUptakeValue;CI=ConfidenceInterval

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Figure 4: ComparisonofReceiveroperatingcharacteristiccurvesofhighestSUVmaxofprimarytumor,largesttumorsizeandhighestSUVmaxofnodeonbaseline18FDGPET/CTasdiseasefreeanddiseaserecurrenceonmetabolicresponseinSCCofheadandneckinfollowupstudies.SE=StandardError;SUV=StandardizedUptakeValue;CI=ConfidenceInterval

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Figure 5: ComparativeanalysisforKaplanMeierSurvivalplotsforprimarytumorsize> 29mmand≤29mminbaseline18FDG PET/CT studies as predictor forrecurrenceinSCCofheadandneckinfollowupstudies.*P<0.05;PTS=PrimaryTumorsize;SE=StandardError;CI=ConfidenceInterval

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Figure 6: ComparativeanalysisforKaplanMeierSurvivalplotsforprimarytumorSUVmax>4.6andSUVmax≤4.6inbaseline18FDG PET/CT studies aspredictorforrecurrenceinSCCofheadandneckinfollowupstudies. *P<0.05;SE=StandardError;CI=ConfidenceInterval

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Figure 7: ComparativeanalysisforKaplanMeierSurvivalplotsfornodalSUVmax>6.2andSUVmax≤6.2inbaseline18FDGPET/CTstudiesaspredictorforrecurrenceinSCCofheadandneckinfollowupstudies.*P<0.05;SE=StandardError;CI=ConfidenceInterval

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   Discussion Top


In Pakistan, HN-SCC is the second most common malignancy in both genders, after breast cancer in females and lung cancer in males.[9] Like other cancers, prognosis of HN-SCC depends largely on the stage of presentation, with nodal metastasis being the single most important factor which reduces long-term survival by 50%.[10] In our studied population, no significant difference was seen between disease free and disease recurrence group for age, male gender predominance, body mass index, and diabetes. This indeed increases the statistical strength of our data. Similarly, lack of significance in acquisition parameters between two PET/CT studies in two groups also minimize the impact these confounding factors on SUVmax calculations.[8] This also highlights the importance of adherence to a standardized imaging protocol.[8]

Our study found positive impact of primary Ts on recurrence in studied population with a cutoff value of >29 mm (≥T2 stage). Possible explanation for this correlation is higher odds of positive margins with increasing Ts[11] and involved surgical margin is an established independent risk factor for higher recurrence.[12] This finding is in concordance with another study published from our institute revealing a poor outcome with tumor volume >23.1 cm3 in patients with HN-SCC.[9] However, there are some published studies which reported no significant association between recurrence and Ts, but the depth of primary tumor invasion.[13] This finding again draws attention of multidisciplinary team toward a meticulous and wide local resection of primary tumor (≥T2) to minimize odds of recurrence.

In this study, we have also evaluated the most commonly used metabolic matrix SUVmax of primary tumor and the most avid neck node. We found that higher SUVmax of primary tumor (cutoff: >4.6) is an independent risk factor for recurrence. SUVmax of primary tumor is one of the frequently reported metrics, showing significant prognostic impact on overall survival, progression-free survival, and locoregional control.[14],[15] One of the pioneer studies in this regard was published by Minn et al. in 1997 and they also found a cutoff SUVmax >9.0 was associated with lower 3-year disease-free survival (DFS: <24%).[16] The difference between their cutoff value (>9.0) with the current study (>4.6) might be due to variation in histological tumor grading and/or imaging protocols. Another study reported significantly lower DFS in patients with higher SUVmax of primary HN-SCC.[5] However, a recent study did not find a significant correlation between high 18FDG uptake in the primary tumor and T-site recurrence using same acquisition protocol in a competing risk scenario.[6] The authors suspected that the effect of a high 18FDG uptake may already be accounted for by inclusion of T-stage in their model.[6] We have also found that SUVmax of the most avid neck node at baseline is an independent risk factor for recurrence with a cutoff >6.2. This indicate higher metastatic tumor burden in the involved node and the presence of nodal metastasis at baseline reduces long-term survival by 50%.[9] Our data are in concordance with a recent study which reveals that high nodal FDG uptake (SUVmax) increases risk of distant metastasis in patients with HNOP-SCC.[6] They found that model including 18FDG uptake (SUVmaxN) had a significantly better absolute risk prediction (Brier score) for M-site recurrence compared with the model without SUVmaxN.[6] Another published study revealed that baseline SUVmax of neck node is a poor prognostic marker.[17] However, a recent study from India failed to find a significant influence of baseline SUVmax of node on overall survival or DFS.[18]

Our study also revealed that SUVmax >6.2 of the most avid node was the strongest predictor of early tumor recurrence and the shortest DFS (8.6 months) compared to Ts and SUVmax of primary tumor in baseline 18FDG PET/CT study. This finding is in concordance with a recently published Danish study which also showed that high nodal FDG uptake increases the risk of N-and M-site recurrence in OPSCC in a competing risk scenario.[6] We are cognizant that presence of nodal metastasis in HN-SCC reduces the long-term survival by 50%[10] and using a SUVmax >6.4 of the most avid node at baseline 18FDG PET/CT would help the multidisciplinary team to plan treatment strategy accordingly.

Strength of our studies are its prospective design, reasonably good sample size, no significant difference in patients' demographic in disease free and recurrence groups and strict adherence to standardized 18FDG PET/CT acquisition protocol. Our study has some limitations such as we did not describe TNM staging explicitly as we had selected patients with M0-disease only (lenient criterion). We also did not mention p-16 and HPV status as these were available in only few patients. Another limitation is that we did not use other 18FDG PET/CT-based metabolic markers (like TLG and MTV) as we know that SUVmax is the most common parameter used worldwide in oncological imaging. Follow-up of our cohort was short, but this is an ongoing study and a subsequent study with larger sample size with longer follow-up will be shared.

We conclude that, in HNOP-SCC, primary Ts (>29 mm), SUVmax of primary tumor (>4.6), and the most avid neck node (>6.2) in baseline 18FDG PET/CT using standardized imaging protocol are the independent predictors of disease recurrence. Furthermore, SUVmax >6.2 of the most avid node predicts the shortest DFS than primary Ts and SUVmax of primary tumor.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Stenson KM. Epidemiology and Risk Factors for Head and Neck Cancer. http://uptodate.com/contents/epidemiology-and-risk-factors-for-head-and-neck-cancer.[Last accessed on 2020 Apr 14].  Back to cited text no. 1
    
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Brizel DM. Different strokes for different folks: New paradigms for staging oropharynx cancer. J Clin Oncol 2015;33:817-8.  Back to cited text no. 3
    
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Imsande HM, Davison JM, Truong MT, Devaiah AK, Mercier GA, Ozonoff AJ, et al. Use of 18F-FDG PET/CT as a predictive biomarker of outcome in patients with head-and-neck non-squamous cell carcinoma. AJR Am J Roentgenol 2011;197:976-80.  Back to cited text no. 4
    
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Machtay M, Natwa M, Andrel J, Hyslop T, Anne PR, Lavarino J, et al. Pretreatment FDG-PET standardized uptake value as a prognostic factor for outcome in head and neck cancer. Head Neck 2009;31:195-201.  Back to cited text no. 5
    
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Jakob S, Christensen JT, Håkansson K, Zamani M, Vogelius IR, Löfgren J, et al. High nodal FDG uptake increases risk of distant metastasis in patients with oropharyngeal squamous cell carcinoma. Eur J Nucl Med Mol Imaging 2020;47:1039-45.  Back to cited text no. 6
    
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Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: Version 2.0. Eur J Nucl Med Mol Imaging 2015;42:328-54.  Back to cited text no. 7
    
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Boellaard R. Need for standardization of 18F-FDG PET/CT for treatment response assessments. J Nucl Med 2011;52 Suppl 2:93S-100S.  Back to cited text no. 8
    
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Kazmi FN, Adil A, Ghaffar S, Ahmed F. Association between tumour volume and recurrence of squamous cell carcinoma of the head and neck. J Pak Med Assoc 2012;62:1129-33.  Back to cited text no. 9
    
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Sanderson RJ, Ironside JA. Squamous cell carcinomas of the head and neck. BMJ 2002;325:822-7.  Back to cited text no. 10
    
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Mohiyuddin SM, Padiyar BV, Suresh TN, Mohammadi K, Sagayaraj A, Merchant S, et al. Clinicopathological study of surgical margins in squamous cell carcinoma of buccal mucosa. World J Otorhinolaryngol Head Neck Surg 2016;2:17-21.  Back to cited text no. 11
    
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Hany E, Craig M, Christine E, Abdulla H. The effect of the surgical margins on the outcome of patients with head and neck squamous cell carcinoma: Single institution experience. Cancer Biol Med 2012;9:29-33.  Back to cited text no. 12
    
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Behcet S, Suphi B, Ilker A, Ibrahim C. Prognostic factors of recurrence and neck metastasis in oral carcinomas. Pak J Med Sci 2016;32:153-6.  Back to cited text no. 13
    
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Rasmussen JH, Håkansson K, Rasmussen GB, Vogelius IR, Friborg J, Fischer BM, et al. A clinical prognostic model compared to the newly adopted UICC staging in an independent validation cohort of P16 negative/positive head and neck cancer patients. Oral Oncol 2018;81:52-60.  Back to cited text no. 14
    
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Bonomo P, Merlotti A, Olmetto E, Bianchi A, Desideri I, Bacigalupo A, et al. What is the prognostic impact of FDG PET in locally advanced head and neck squamous cell carcinoma treated with concomitant chemo-radiotherapy? A systematic review and meta-analysis. Eur J Nucl Med Mol Imaging 2018;45:2122-38.  Back to cited text no. 15
    
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Minn H, Lapela M, Klemi PJ, Grénman R, Leskinen S, Lindholm P, et al. Prediction of survival with fluorine-18-fluoro-deoxyglucose and PET in head and neck cancer. J Nucl Med 1997;38:1907-11.  Back to cited text no. 16
    
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Oruc Z, Emin BM, Kaplan MA, Urakcı Z, Küçükoner M, Isıkdogan A. Association between standardized uptake value and survival in patients with locally advanced or metastatic squamous cell head and neck cancer. J Oncol Sci 2016;1:1-4.  Back to cited text no. 17
    
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Sarbani G, Naveen M, Venkatesh R, Nilendu P, Tejpal G, Ashwini B, et al. Prognostic value of response assessment fluorodeoxyglucose positron emission tomography-computed tomography scan in radically treated squamous cell carcinoma of head and neck: Long-term results of a prospective study. J Can Res Ther 2019;15:596-603.  Back to cited text no. 18
    


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