Annals of Oncology Advance Access originally published online on August 22, 2007
Annals of Oncology 2007 18(10):1698-1703; doi:10.1093/annonc/mdm270
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© 2007 European Society for Medical Oncology
head and neck cancer |
Combined 18F-fluorodeoxyglucose-positron emission tomography and computed tomography as a primary screening method for detecting second primary cancers and distant metastases in patients with head and neck cancer
1 Department of Otolaryngology
2 Department of Nuclear Medicine
3 Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
* Correspondence to: Dr. J.-L. Roh, Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-dong, Songpa-gu, Seoul 138-736, Republic of Korea. Tel: +82–2–3010–965; Fax: +82–2–489–2773; E-mail address: rohjl{at}amc.seoul.kr
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Background: The aim of this study was to evaluate the ability of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) to detect second primary cancers and distant metastases in patients with head and neck cancer (HNC).
Patients and methods: Patients with previous untreated HNC, between 2004 and 2005, underwent head and neck CT and whole-body FDG-PET/CT, before and at fixed intervals after therapy, for staging and detection of second primary cancers and distant metastases. Patients with malignant or equivocal findings on FDG-PET/CT underwent further imaging, endoscopy and/or biopsy.
Results: Of the 349 eligible patients (267 men and 82 women), 14 (4.0%) had second primary cancers and 26 (7.4%) had distant metastases at initial staging or during mean follow-up of 15 months after treatment. FDG-PET/CT correctly identified second cancers or distant metastases in 39 of these 40 patients; there was one false negative and 23 false positive FDG-PET/CT results. Therefore, FDG-PET/CT had a sensitivity of 97.5%, a specificity of 92.6%, a positive predictive value of 62.9% and a negative predictive value of 99.7% in detecting second primary cancers and distant metastases.
Conclusion: Combined FDG-PET/CT is useful as a primary method for detecting second cancers and distant metastases in patients with HNC.
Key words: head and neck cancers, second primary cancers, distant metastasis, FDG-PET/CT
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The incidence of distant metastases in patients with head and neck cancers (HNC) is smaller than in other primary malignancies, ranging from 4 to 25%, with the lungs, bones and liver being the most frequent sites [1–3]. Although locoregional control of disease in HNC patients has improved, it is not matched by improvements in survival, due to an increase in deaths from distant metastases and the emergence of second primary tumors [1]. Distant metastases usually occur late during the course of the disease, whereas second primary cancers are found even in patients with early-stage HNC [4]. Since second primary cancers and distant metastases are the leading causes of treatment failure and death in patients with HNC, early detection is essential for precise tumor staging, optimal management and patient counseling.
Tests used to detect second primary cancers and distant metastases in HNC patients have included chest radiographs, chest computed tomography (CT), ultrasound or CT scan of the liver, skeletal scintigraphy and panendoscopy [5,6]. The chest CT scan has been the single most important diagnostic technique because the lung is the most common site of second or metastatic cancers of patients with HNC [5,6]. However, a more sensitive method that screens the whole body may be more accurate [7,8]. 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) has shown sensitivity in detecting unsuspected second primary tumors and distant metastases, as well as in identifying locoregional disease [8–10]. Moreover, the combination of FDG-PET and CT has been found superior to FDG-PET alone in screening for second primary cancers, since the combination provides an accurate anatomic localization along with concurrent metabolic information [11]. Although FDG-PET is used extensively in oncological practice, little is known about the ability of combined FDG-PET/CT to identify second primary cancers and/or distant metastases in patients with HNC. We therefore evaluated the ability of combined FDG-PET/CT to detect second primary cancers and distant metastases in a large number of consecutive HNC patients at the time of initial tumor staging and after treatment.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients and study design
We performed whole-body FDG-PET/CT for primary staging work-up and follow-up in 425 consecutive HNC patients newly diagnosed between January 2004 and December 2005 at our institution. In addition, all patients underwent contrast-enhanced CT or MRI of the head and neck as well as careful physical and endoscopic examinations of the upper aerodigestive tract and the neck. The head and neck CT/MRI and whole-body FDG-PET/CT were performed in all patients before and at fixed interval (about every 6 months) after treatment. To identify second primary or distant metastatic cancers, we utilized a rational approach, in which additional imaging and biopsies were based on whole-body FDG-PET/CT findings. For example, if FDG-PET/CT resulted in a suspicion of malignant lesions on the lung, we performed chest CT and needle or bronchoscopic biopsy [11]. We excluded those patients who rejected further work-ups for confirmation or follow-up FDG-PET/CT imaging; patients with thyroid cancer, lymphoma or primary malignancy of unknown origin; and patients with a prior history of HNC. During the study period, a total of 349 eligible patients were enrolled into this study. Clinicopathologic information was extracted from patients' medical records. This study was reviewed and approved by the Ethics Review Committee of our institute and informed consent was obtained from each patient.
combined FDG-PET/CT imaging
Combined FDG-PET/CT was performed using a Biograph Sensation 16 scanner (Siemens/CTI, Knoxville, TN), which provides an in-plane spatial resolution of 6.0 mm, an axial field view of 16.2 cm and three-dimensional image acquisition. Patients were required to fast for 6 hours prior to scanning, and whole-body PET scanning from the skull base to the upper thighs was performed approximately 1 hour after an intravenous injection of 555 MBq of FDG. Whole-body CT scanning was performed in spiral mode with 100 mAs, 120 kV, a section width of 5 mm, 0.75 mm collimation, and a table feed of 15 mm/gantry rotation, immediately preceding the acquisition of PET emission data (2 minutes per bed position). Intravenous contrast was not used during the CT scanning. FDG-PET images were reconstructed using CT data for attenuation correction with the OSEM algorithm (2 iterations, 16 subsets) and 6.0 mm Gaussian filter using a 128 x 128 matrix. Visible lesions with increased tracer uptake were identified and their uptake was quantified.
image interpretation
The combined FDG-PET/CT images were interpreted by visual inspection by one experienced nuclear medicine physician who had access to the relevant clinical information. Foci showing increased FDG uptake were evaluated by comparison to background and blood pool activity and the presence of morphological alterations on CT images. The degree of suspicion of malignant involvement was based on qualitative visual interpretation of the images and a semiquantitative measure of relative FDG uptake within the regions of interest. Due to a patient's medical history, physical findings and/or imaging pattern, some positive scans were interpreted as indicative of benign conditions.
If abnormal focal FDG uptake was detected at a site distant from the primary HNC, the specialists in charge were notified and confirmation was obtained by additional diagnostic methods or biopsy. With lung and liver lesions, where metastases frequently occur, only single nodule or mass with increased FDG uptake or with pathology different from primary HNC was considered suggestive of a second primary malignancy, whereas multiple nodules or masses with increased FDG uptake were generally considered metastases [11]. All these lesions suspicious of malignancy on PET/CT were confirmed by further imaging, endoscopic work-ups and biopsy. In addition, distant metastases were interpreted as true positives if follow-up FDG-PET/CT and other imaging specific for the region showed tumor progression or if the biopsy revealed a malignancy.
When the primary tumor and suspected second malignancy were composed of an identical cell type, the tumor board, consisting of radiologists/nuclear medicine staff, pathologists and clinicians, determined whether it was a metastasis or a second primary cancer after considering the comparative histological findings, radiological appearance, and the stage and biological behavior of the primary tumor. True negative or false results of FDG-PET/CT were confirmed by follow-up imaging at regular intervals (within 6 months, 1 and 2 years) after therapy in all patients and when any suspicious lesions were found in the patients.
statistical analysis
FDG-PET/CT results visually interpreted as malignant were considered positive, whereas benign or equivocal lesions were considered negative. True/false positives and negatives were defined as based on the results of the above-mentioned confirmation methods and the FDG-PET/CT and other imaging follow-ups. The sensitivity, specificity, accuracy and predictive values of FDG-PET/CT were calculated. However, the sensitivity, specificity, accuracy and predictive values of conventional or additional diagnostic work-ups were not calculated because these latter tests were performed only in a fraction of the patients involved in this study, particularly those suspected of having a second primary or metastatic lesion on FDG-PET/CT.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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In the final analysis, 349 eligible patients consisted of 267 men and 82 women, with mean age of 60.3 years (Table 1). The primary HNC most frequently occurred in the larynx (32.1%), followed by the oral cavity, oropharynx, nasopharynx and hypopharynx, with the most common pathology being squamous cell carcinoma (81.1%) and with 71.1% advanced stages III and IV. The histological subtype of primary HNC was not described in detail because of various types of histology, particularly in the salivary gland tumors.
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Of the 349 patients, 40 (11.5%) had second primary cancers (n = 14, 4.0%) or distant metastases (n = 26, 7.4%) (Table 2). These lesions were detected in 18 patients at initial staging and in 22 at a mean of 8.6 months (range 3–21 months) after the diagnosis of the primary head and neck tumors. All the second primary cancers were confirmed by both imaging workups and histology. Second primary cancers were located in the lungs in seven patients, the thyroid in two, and the nasal cavity, esophagus, colon, rectum, and stomach in one each. The most common metastatic sites were the lungs (n = 18), mediastinum (n = 6), bones (n = 9) and liver (n = 6). The medians (range) in number and size of pulmonary metastases were 4.9 (1–29) and 1.8 (0.9–3.6) cm, and those of metastatic mediastinal lymphadenopathy were 4.5 (1–17) and 1.9 (1.1–3.3) cm.
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FDG-PET/CT correctly identified the lesions in 39 of the 40 patients with second primary or distant metastatic malignancies (Figure 1). The only exception was a 67-year-old male patient with a buccal cancer of pT2N2b stage, a mucoepidermoid carcinoma, in which FDG-PET/CT did not correctly identify metastatic lesions on the lungs and gluteus muscle at initial staging; these lesions were suspected on other contrast-enhanced CT scans and confirmed by needle biopsies (Figure 2). FDG-PET/CT resulted in false positive interpretations of second primary or metastatic tumors at 24 sites in 23 patients, consisting of the lungs (n = 5), mediastinum (n = 5), bones (n = 4), colon (n = 3), thyroid (n = 2), prostate (n = 2), axilla (n = 1), liver (n = 1) and esophagus (n = 1). All false positives were corrected by further imaging, follow-up FDG-PET/CT and/or histological confirmation. Therefore, FDG-PET/CT at initial staging and follow-up had a sensitivity of 97.5% (95% confidence interval [CI], 86–99%), a specificity of 92.6% (95% CI, 89–95%), an accuracy of 93.1% (95% CI, 88–96%), a positive predictive value of 62.9% (95% CI, 49–74%), and a negative predictive value of 99.7% (95% CI, 98–99%).
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Conventional imaging work-ups correctly diagnosed second primary or metastatic tumors in 36 of 40 patients, with the remaining four diagnostically confirmed by further endoscopic or ultrasound (US)-guided biopsy, all four had suspicious lesions on FDG-PET/CT. Since these imaging methods, including chest CT, abdominal CT, abdominal US, and skeletal scintigraphy, were performed only in patients suspected of having these lesions, but not in other patients, we could not compare the diagnostic accuracy of these methods with those of FDG-PET/CT.
The mean clinical follow-up duration after the diagnosis of the primary head and neck tumor was 15.3 ± 6.2 months. Of the 14 second primary tumors, 10 (71.4%) were early stage. At last follow-up, seven of these patients (50.0%) showed no evidence of either primary HNC or second primary tumors that were staged as T1N0 in three patients and T2N0 in four patients at the time of diagnosis, although the follow-up period was not long enough to estimate survival (Table 2). In contrast, the prognosis of the 26 patients with distant metastases was much poorer, showing that most patients were alive with disease (n = 10) or died of disease (n = 9) at the last follow-up, except for four patients with primary nasopharyngeal carcinomas.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Second primary cancers are the chief cause of death among patients with early-stage disease, while distant metastases hamper the survival of patients with advanced-stage HNC, thus making the early detection of second primary or metastatic tumors necessary for enhanced survival. In the current study, we found that FDG-PET/CT had a high sensitivity of 97.5% and a negative predictive value of almost 100% for detecting second primary cancers or distant metastases, suggesting that combined whole-body FDG-PET/CT is useful in screening for these tumors in HNC patients at initial staging or after treatment. The positive predictive value of FDG-PET/CT for detecting second primary or distant metastatic tumors, however, was only about 60%, suggesting that additional diagnostic methods are necessary to exclude false-positive results.
We found that second primary cancers and distant metastases occurred in 4.0% and 7.4%, respectively, of a large number of patients (n = 349) with primary HNC over 2 years. Synchronous second primary tumors (i.e. tumors detected within 6 months) have been reported to occur in 1.4% to 18% of patients with HNC, and seem to depend on racial, environmental and occupational factors [10,12–14]. The majority of all second primary tumors arise metachronously (i.e. at least 6 months after initial presentation of the index tumor), at an annual rate of 2.8% [12]. In our study, the second primary tumors were found in 10 of 349 patients (2.8%) at initial staging and in four patients (1.2%) during the follow-up duration of mean 15 months, suggesting that additional second primary tumors might be detected with a longer follow-up period. Ten of these second primary tumors were present in regions below the clavicle, most in the lungs (n = 7), with only four in other head and neck regions. These results suggest that a sensitive, whole-body screening technique such as FDG PET or PET/CT is required to detect second primary cancers. Using conventional methods, these tumors are not detected until they attain advanced stage [10,11]. Although panendoscopy under general anesthesia has been recommended for early diagnosis, it is both invasive and results in low yield. Our results suggest that FDG-PET/CT may increase the rate of detection of second primary tumors. The second primary cancers detected by FDG-PET/CT might be clinically irrelevant diseases, however, the FDG-PET/CT scanning for detecting second primary tumors can assist in planning proper therapy for these patients.
The overall incidence of clinically detected distant metastases in HNC is 4 to 25% [1–3]. In the present study, 26 of 349 HNC patients (7.4%) presented with distant metastases, eight at initial staging and 18 during follow-up, with most of the latter presenting within 1 year after therapy. Persistent or recurrent locoregional HNC may contribute to the occurrence of distant metastases, thereby lowering survival. FDG-PET/CT scan had a high sensitivity in detecting metastatic lesions below the clavicle. The false-negative and false-positive results of FDG-PET/CT for the detection of second primary tumors or distant metastasis were found only in 1 and 23 patients, respectively, which was remarkably low (6.9%) in the present study. The low positive predictive value (60%) was mainly due to the low prevalence of metastatic lesions in HNC. Although the false-positive rate was not significantly high in our study, these results may lead to upstaging to M1 and misguide in the treatment of these patients. The false-positives may be uncommonly seen in the conventional imaging work-ups such as chest or abdomen CT, less expensive and more readily available compared with FDG-PET/CT scan [5,6,15,16]. Thus, the false-positives should be confirmed by conventional imaging and/or biopsy to avoid false upstaging to M1.
One important limitation of our study was the lack of data in HNC patients with no FDG uptake in their thorax or other body areas because conventional metastatic work-ups were not routinely performed. Although the prevalence of second primary or distant metastatic tumors in these patients seems to be low, subclinical disease can be present. However, true negative or false results of FDG-PET/CT were confirmed by regular follow-up images after treatment in all patients of our study. Only patients with second or metastatic tumors indicative of malignant or equivocal findings on FDG-PET/CT underwent further imaging and endoscopic biopsy. In oncological practice, it may be ethically problematic and not cost-effective for all HNC patients, even those with negative or benign-looking second tumors on FDG-PET/CT, to undergo conventional imaging, endoscopy and biopsy to detect the second primary or metastatic tumors, either at initial staging or at post-treatment follow-up. For some of these patients, close follow-up with imaging may be better. Our findings suggest that using FDG-PET/CT to guide further diagnostic methods may avoid multiple invasive procedures, decreasing the cost per patient. Combined FDG-PET/CT may also be superior to FDG-PET for screening second primary cancers [11,17], suggesting that FDG-PET/CT may be better for accurate initial staging in oncological practice, whereas other imaging methodologies can be considered supplementary in this setting. The accuracy of FDG-PET/CT may increase by the use of intravenous contrast for the FDG-PET/CT scanning, as this was not used in our study but is now the standard of care in some institutions.
In conclusion, we found that combined FDG-PET/CT is useful as a primary screening method for detecting second primary cancers and distant metastases in patients with primary HNC. While FDG-PET/CT had high sensitivity, specificity, and negative predictive value, it had a lower positive predictive value, suggesting that additional diagnostic methods are essential to rule out false positives and to avoid false upstaging to M1 for appropriate therapeutic planning. The early detection of second primary tumors or distant metastases may have major consequences for prognosis and survival.
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Acknowledgements |
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This work was supported by the Ministry of Science and Technology F104AA010009-06A0101-00910 (S.Y. Kim) and the Ministry of Health & Welfare, the National R&D Program for Cancer Control, Grant No. 0620160-1 (J.-L. Roh), Republic of Korea.
Received for publication March 9, 2007. Revision received May 1, 2007. Accepted for publication May 2, 2007.
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