|Year : 2014 | Volume
| Issue : 4 | Page : 922-926
Prognostic significance and predictive performance of volume-based parameters of F-18 FDG PET/CT in squamous cell head and neck cancers
Sait Sager1, Sertaç Asa1, Mehmet Yilmaz2, Lebriz Uslu1, Betul Vatankulu1, Metin Halaç1, Kerim Sönmezoglu1, Bedii Kanmaz1
1 Department of Nuclear Medicine, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey
2 Department of Head and Neck Surgery, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey
|Date of Web Publication||9-Jan-2015|
Department of Nuclear Medicine, Istanbul University, Cerrahpasa Medical Faculty, Cerrahpasa, Fatih, Istanbul
Source of Support: We would like to thank the Scientific Research
Projects Coordination Unit of Istanbul University, Conflict of Interest: None
Aim: It has been previously reported that metabolic tumor volume on positron emission tomography-computed tomography predicts disease recurrence and death in head-and-neck cancer. In this study, we assessed the prognostic value of metabolic tumor volume measured using F18-Fluorodeoxyglucose PET/CT in patients with head and neck squamous cell carcinoma.
Materials and Methods: We analyzed the imaging findings of 74 patients (age 57 ± 16) retrospectively, with head and neck cancer who underwent PET/CT scan for staging and after treatment. Forty-tree patients had nasopharynx, 15 patients had hypopharynx, 9 patients had larynx, and 7 patients had oropharynx cancer. The MTVs of primary sites with or without lymph nodes were measured, and outcomes were assessed using the treatment response evaluation by the Response Evaluation Criteria in Solid Tumors and recurrence events during follow-up.
Results: A total of 48 patients had complete response or no recurrence was detected as of in the last follow-up. Of the first PET/CT scan, the median primary tumor SUVmax was 18.8 and the median nodal SUVmax was 13.4. The median primary tumor MTV% 50s ranged from 11.12 cm 3 to 16.28 cm 3 , and the MTV after the therapy ranged from 1.18 cm 3 to 3.51 cm 3 .
Conclusion: Metabolic tumor volume (MTV) represents tumor burden, which shows F18-Fluorodeoxyglucose uptake and has a potential value in predicting short-term outcome and disease-free survival in patients with head and neck cancer.
基于容积的 F-18 FDG PET／CT参数在头颈部鳞癌中的预后意义和疾病的预示
结果：直到最后一次随访，共48例患者完全缓解或没有检测到复发。第一次PET / CT扫描中，平均原发肿瘤SUVmax为18.8，中位淋巴结SUVmax为13.4。中位原发肿瘤 MTV% 50s从11.12cm3到16.28cm3，而治疗后MTV的范围从1.18cm3到3.51cm3。
关键词：代谢肿瘤体积，最大标准摄取值，PET / CT
Keywords: Metabolic tumor volume, maximum standardized uptake value, PET/CT
|How to cite this article:|
Sager S, Asa S, Yilmaz M, Uslu L, Vatankulu B, Halaç M, Sönmezoglu K, Kanmaz B. Prognostic significance and predictive performance of volume-based parameters of F-18 FDG PET/CT in squamous cell head and neck cancers. J Can Res Ther 2014;10:922-6
|How to cite this URL:|
Sager S, Asa S, Yilmaz M, Uslu L, Vatankulu B, Halaç M, Sönmezoglu K, Kanmaz B. Prognostic significance and predictive performance of volume-based parameters of F-18 FDG PET/CT in squamous cell head and neck cancers. J Can Res Ther [serial online] 2014 [cited 2019 Nov 20];10:922-6. Available from: http://www.cancerjournal.net/text.asp?2014/10/4/922/137968
| > Introduction|| |
F18-Fluorodeoxyglucose (FDG) PET/CT is widely used for staging and planning the therapy in patients with head and neck cancer (HNC). , Unexpected distant metastases can change staging and whole therapy planning, which just cannot be detected by other imaging methods.  It can also be used for detecting answers to therapy and makes advantage for detecting residual metabolic activity, which cannot be detected by only CT scan.  Standardized uptake value (SUV), is a semi-quantitative parameter in F18-FDG PET/CT, known to be a significant factor for prognosis and treatment guidance in many malignancies. , SUVmax is a value that shows maximum FDG uptake in the cells, which is mostly proven as a predictor for the aggressiveness of most of cancer types.  SUVmax can be considered to be a single-pixel ROI, and it is highly dependent on the statistical quality of the images and the size of the maximal pixel. SUVmax variability increases with the matrix size as well as the decrease in count statistics.  SUVmax represents the maximum metabolic activity of the tumor, and variations in its value represent the most clinically relevant change due to therapy; however, the reliability of SUVmax as a single pixel measurement is subject to fluctuations. 
Tumor burden or tumor volume usually does not show exact tumor stage because the size of the tumor in its greatest dimensions is not representative of the three-dimensional tumor volume.  Two-dimensional parameter of a tumor is an important factor for tumor burden or in surgical treatment; however, three-dimensional volumetric data has become another important factor to be considered in radiotherapy or chemotherapy.
Recent studies showed that another parameter, which is called metabolic tumor volume (MTV) that shows metabolic tumor burden, can be much more helpful and can be useful for predicting patients' outcome before therapy. , Also, we suggest that it can be an option as a prognostic factor, additionally helpful to discriminate the post-radiotherapy change and recurrence. Therefore, in this study, we try to evaluate the answer for chemo-radiotherapy with measuring SUV values and MTV with PET/CT scan in the follow-up patients diagnosed with squamous cell head and neck cancer (HNC) and also try to analyze the relation between two parameters.
| > Materials and methods|| |
We analyzed the data of 74 patients (age 57 ± 16) retrospectively, with biopsy-proven head and neck squamous cell carcinoma, who underwent PET/CT scan for staging and after treatment. Fifty-four patients were males, and 20 patients were females. The primary tumor localizations were nasopharynx for 43 patients, hypopharynx for 15 patients, larynx for 9 patients, and oropharynx for 7 patients. Patients were included in this study if they had both a pre-treatment PET/CT study for staging and had a post-treatment PET/CT for follow-up. In the follow-ups, patients after the surgery, radiotherapy (RT) or chemotherapy (CT), new PET/CT images were performed and compared with initial study. Also, patients' follow-up times were registered to analysis and predicting short-term outcome, disease-free survival (DFS), and overall survival (OS).
PET/CT images were obtained 75 minutes after intravenous administration of approximately 450-580 MBq of F-18 FDG using a PET scanner. All patients fasted at least 6 hours before injection, and their glucose level were under control. PET, CT, and fused PET/CT images were reviewed in axial, coronal, and sagittal planes. To view the images, PET and CT datasets were transferred to an independent computer workstation by DICOM (Digital Imaging and Communications in Medicine) transfer. Semi-quantitative and volumetric analyses of the primary tumors were performed by two nuclear medicine physicians using the volume viewer software on a GE Advantage Workstation 4.6 (GE Healthcare, Milwaukee, WI, USA), which provides a convenient and automatic way to delineate the volume of interest using an isocontour threshold method based on SUVmax results.
Lesions with SUVmax higher than 2.5 were accepted as positive. MTV was defined as the tumor volume >50% of maximum SUVmax and also calculated for the primary tumor, nodal disease, and composite of primary tumor with lymph nodes. The MTVs of primary sites with or without lymph nodes were measured, and outcomes were assessed using the treatment response evaluation by the Response Evaluation Criteria in Solid Tumors and recurrence events during follow-up. The Kaplan-Meier test and time-dependent ROC curve analysis were done to assess the DFS and OS analysis.
| > Results|| |
[Table 1] shows the clinical characteristics of all patients. The PET/CT scan did not show any abnormal FDG uptake (SUVmax <2.5, metabolic complete response) in 48 patients (64.8%). In patients with complete response (CR), no distant metastasis was detected. After the completion of treatment, partial response (PR) was achieved in 14 (18.9%) patients. Eight patients' imaging showed complete metabolic response in tumor but partial metabolic response in lymph nodes. In 3 patients (4.1%), stable disease (SD) was seen, and in 9 patient (12.2%), progressive disease (PD) was seen. The total median of tumor pre-treatment SUVmax was 18.8, and the median lymph nodes SUVmax was 13.4. In initial PET/CT study, 21 patients (28.4%) had T1 disease, 27 patients (36.6%) had T2 disease, 17 patients (22.8%) had T3 disease, and 9 patients (12.2%) had T4 disease.
The median threshold MTV was calculated before and after treatment. The median primary tumor MTV ranged from 11.12 to 16.28 cm  , and the MTV after the therapy ranged from 1.18 to 3.51 cm  . There was no correlation between primary tumor MTV and lymph node MTV.
The major group of our study was nasopharyngeal carcinoma patients. Forty-three of the 74 patients (58.1%) were NPC group. Thirty-five of 43 nasopharyngeal carcinoma patients had CR (81.3%) after the therapy regimens. MTV larger than 13 cm  had a significantly lower number of CR [Figure 1] and [Figure 2].
|Figure 1: Seventeen-year-old female patient with nasopharynx cancer was referred to FDG PET/CT imaging for staging and therapy planning of primary disease. She had a primary tumor on the right side of the nasopharynx with increased FDG uptake and calculated SUVmax was 15.0. Primary tumor metabolic tumor volume was calculated as 7.22 cm3. In the right neck area, she had a bulky lymphadenomegalies with increased FDG uptake and calculated SUVmax was 22.7 and metabolic tumor volume was 72.2 cm3|
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|Figure 2: Four weeks after the radiotherapy treatment, another FDG PET/CT imaging was performed to evaluate the therapy. There was no FDG uptake on the nasopharynx area and right side of the neck area. There was no increased pathological FDG uptake seen in other parts of the body|
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The median follow-up time for all patients was 23 months (3-41 months). Six patients had died in the follow-up. Disease-free survival (DFS) and overall survival (OS) were calculated from the date of diagnosis. An increase in MTV in the follow-up study was associated with an increased hazard of disease progression (DFS) and OS, with hazard ratios of 2.5 (P > 0.001) and 2.0 (P > 0.002), respectively. Disease progression-free survival was significantly longer in patients with complete metabolic response measured at post-therapy PET/CT [Table 2].
|Table 2: Disease - Free Survival (DFS) and overall survival (OS) of 74 patients |
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| > Discussion|| |
F18-FDG PET imaging combined with computed tomography (CT) plays an important role in staging and treatment planning in patients with head and neck cancer (HNC).  PET/CT imaging shows metabolic modifications, which are well-known to occur before morphologic changes; therefore, functional imaging allows an evaluation of the tumor metabolic response during radiotherapy or chemotherapy earlier than morphologic changes. , Previous studies indicate that PET/CT shows a significant correlation with pathological response following induction and concurrent chemoradiotherapy. 
Assessment of change in tumor size is an important feature of the clinical evaluation of tumor therapies. On conventional anatomical imaging methods, tumor size is estimated by only a one dimensional measurement of the largest tumor diameter, as in the TNM staging system or in the RECIST system. Only one dimensional measurement does not represents the real tumor size or tumor burden, because a tumor may not always have a uniform shape and may be highly asymmetrical with non-viable tissues such as areas of necrosis or fibrotic scar.  With the advance of F18-FDG PET/CT imaging, functional assessment and volumetric-based parameters could potentially be applied routinely in clinical practice.
Maximum standardized uptake value (SUVmax), a semi-quantitative parameter in F18-FDG-PET/CT, represents the maximum metabolic activity of the tumor and represents the most clinically relevant change due to therapy.  Also, it is known to be a significant factor for prognosis and treatment guidance in many malignancies. Several patient-related factors could influence FDG uptake and affect SUVmax results such as partial volume effect, image resolution, noise, attenuation correction, reconstruction methods, time between tracer injection and imaging, normalization factors, and plasma glucose level. , Discrimination between residual tumor and normal tissue is important in post-therapy PET/CT scan. For example, imaging done too soon after treatment will be heavily influenced by post-radiation inflammation.
In our study, we have demonstrated that the volume-based parameter MTV of PET is better than tumor size in survival prediction. In these recent studies, it is shown that volume-based parameters of PET/CT imaging such as MTV and TLG (total lesion glycolysis) were significantly associated with an increased risk of recurrence and increased risk of death. Also, as it is shown in our study, the same studies revealed that SUVmax was not a significant prognostic factor for both DFS and OS. Moeller et al. conducted a prospective trial evaluating the prognostic impact of SUVmax in 98 patients with HNCs, and they found that SUVmax was not a useful prognostic factor for most patients like our study.  Xie P. et al. found that there was a high correlation between primary MTV and patient outcome.  Hu et al. and our study showed that increased nodal MTV was correlated with a higher rate of distant metastatic disease.  MTV represents tumor tissues showing active F-18 FDG uptake.
With the advance of F18-FDG PET/CT imaging, functional assessment and volumetric-based parameters could potentially be applied routinely in clinical practice. Modern PET/CT scanners provide three-dimensional metabolic volumetric images. The metabolic tumor burden measurements including MTV have been developed because they incorporate both metabolic activity and tumor volume. It has also been demonstrated that baseline gross tumor volume, determined by manual contouring on X-ray computed tomography (CT) images as part of 3D conformal radiation treatment planning, predicts overall and cause-specific survival. In multiple studies, the manual or semi-automatic measurement of the baseline MTV has been shown to be better than the SUV in predicting patients' prognosis in small cell lung cancer, head and neck cancer, esophageal cancer, and thyroid cancer in locally advanced stages with or without metastasis. Many studies showed that MTV shows metabolic tumor burden and could be useful for predicting patients' outcome before and after therapy as is mentioned in our study. ,
As a result, our study showed that MTV could be a potential predictor of short-term outcome and a prognostic factor for DFS in patients with HNCs treated after the surgery or chemo-radiotherapy. However, one of the limitations of present study is that the automated contouring method could incorporate non-cancerous areas nearby the primary lesion so that MTV would be overestimated or underestimated.
| > Conclusion|| |
Metabolic tumor volume (MTV) represents tumor burden, which shows F18-FDG uptake. It represents the dual characteristics of three-dimensional volumetric data and the metabolic activity of tumor tissue. In this study, we found that PET/CT scan is a valuable way to understand the answer for treatment in the follow-up. Especially with measuring metabolic tumor volume, it can be effective to understand metabolic tumor response and also detecting for distant metastasis.
| > References|| |
Schmid DT, Stoeckli SJ, Bandhauer F, Huguenin P, Schmid S, von Schulthess GK, et al
. Impact of positron emission tomography on the initial staging and theraphy in locoregional advanced squamous cell carcinoma of the head and neck. Laryngoscope 2003;113:888-91.
Ford EC, Herman J, Yorke E, Wahl RL. 18F-FDG PET/CT for image-guided and intensity-modulated radiotheraphy. J Nucl Med 2009;50:1655-65.
Laubenbacher C, Saumweber D, Wagner-Manslau C, Kau RJ, Herz M, Avril N, et al
. Comparison of fluorine-18-fluorodeoxyglucose PET, MRI and endoscopy for staging head and neck squamous cell carcinomas. J Nucl Med 1995;36:1747-57.
Schwartz DL, Ford E, Rajendran J, Yueh B, Coltrera MD, Virgin J, et al
. FDG-PET/CT imaging for preradiotherapy staging of headand-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2003;61:129-36.
Davies A, Tan C, Paschalides C, Barrington SF, O'Doherty M, Utley M, et al
. FDG-PET maximum standardised uptake value is associated with variation in survival: Analysis of 498 lung cancer patients. Lung Cancer 2007;55:75-8.
Kostakoglu L, Goldsmith SJ. 18F-FDG PET evaluation of the response to therapy for lymphoma and for breast, lung, and colorectal carcinoma. J Nucl Med 2003;44:224-39.
Mac Manus MP, Hicks RJ, Ball DL, Kalff V, Matthews JP, Salminen E, et al
. F-18 fluorodeoxyglucose positron emission tomography staging in radical radiotherapy candidates with nonsmall cell lung carcinoma: Powerful correlation with survival and high impact on treatment. Cancer 2001;92:886-95.
Shah B, Srivastava N, Hirsch AE, Mercier G, Subramaniam RM. Intra-reader reliability of FDG PET volumetric tumor parameters: Effects of primary tumor size and segmentation methods. Ann Nucl Med 2012;26:707-14.
Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors. J Nucl Med 2009;50 Suppl 1:122-50S.
Ball DL, Fisher R, Burmeister B, Graham P, Joseph D, Penniment M, et al
. Stage is not a reliable indicator of tumor volume in non-small cell lung cancer: A preliminary analysis of the Trans-Tasman Radiation Oncology Group 99-05 database. J Thorac Oncol 2006;1:667-72.
La TH, Filion EJ, Turnbull BB, Chu JN, Lee P, Nguyen K, et al
. Metabolic tumor volume predicts for recurrence and death in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2009;74:1335-41.
Allal AS, Dulguerov P, Allaoua M, Haenggeli CA, El-Ghazi EL, Lehmann W, et al
. Standardized uptake value of 2-[(18) F] fluoro-2-deoxy-Dglucose in predicting outcome in head and neck carcinomas treated by radiotherapy with or without chemotherapy. J Clin Oncol 2002;20:1398-404.
Avril NE, Weber WA. Monitoring response to treatment in patients utilizing PET. Radiol Clin North Am 2005;43:189-204.
Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, et al
. Measurement of clinical and subclinical tumour response using [18 F]-fluorodeoxyglucose and positron emission tomography: Review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 1999;35:1773-82.
Kikuchi M, Shinohara S, Nakamoto Y, Usami Y, Fujiwara K, Adachi T, et al
. Sequential FDG-PET/CT after neoadjuvant chemotherapy is a predictor of histopathologic response in patients with head and neck squamous cell carcinoma. Mol Imaging Biol 2011;13:368-77.
Sorensen AG, Patel S, Harmath C, Bridges S, Synnott J, Sievers A, et al
. Comparison of diameter and perimeter methods for tumor volume calculation. J Clin Oncol 2001;19:551-7.
Moeller BJ, Rana V, Cannon BA, Williams MD, Sturgis EM, Ginsberg LE, et al
. Prospective risk-adjusted [18F] Fluorodeoxyglucose positron emission tomography and computed tomography assessment of radiation response in head and neck cancer. J Clin Oncol 2009;27:2509-15.
Xie P, Yue JB, Zhao HX, Sun XD, Kong L, Fu Z, et al
. Prognostic value of 18F-FDG PET-CT metabolic index for nasopharyngeal carcinoma. J Cancer Res Clin Oncol 2010;136:883-9.
Huang SH, O'Sullivan B. 2010 Multidisciplinary Head and Neck cancer Symposium. Expert Rev Anticancer Ther 2010;10:651-3.
Tang C, Murphy JD, Khong B, La TH, Kong C, Fischbein NJ, et al
. Validation that metabolic tumor volume predicts outcome in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2012;83:1514-20.
Chu KP, Murphy JD, La TH, Krakow TE, Iagaru A, Graves EE, et al
. Prognostic value of metabolic tumor volume and velocity in predicting head-and-neck cancer outcomes. Int J Radiat Oncol Biol Phys 2012;83:1521-7.
[Figure 1], [Figure 2]
[Table 1], [Table 2]