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Improved Detection of Second Primary Cancer Using Integrated [¹⁸F] Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography for Initial Tumor Staging

From the Departments of Nuclear Medicine, Radiology, Medicine, Thoracic Surgery, and Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Address reprint requests to Byung-Tae Kim, MD, Department of Nuclear Medicine, Samsung Medical Center, 50 Ilwon-dong, Kangnam-ku 135-710 Seoul Republic of Korea; e-mail: btnm.kim{at}samsung.com

	ABSTRACT

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PURPOSE: This study evaluated prospectively the value of integrated whole-body positron emission tomography and computed tomography (PET/CT) using [¹⁸F] fluorodeoxyglucose (FDG) in detecting a second primary cancer at the time of the initial staging in comparison with a conventional staging work-up (CSW).

METHODS: The participants were 547 patients diagnosed with cancer who underwent FDG PET/CT imaging for the initial staging. An additional diagnostic evaluation was performed when there were abnormal findings indicative of a second primary cancer on either PET/CT or CSW considering the site and the biologic behavior of the alleged primary tumor.

RESULTS: A total of 27 second primary malignant tumors were identified in 26 of the 547 patients (4.8%). FDG PET/CT found 45 lesions indicative of a second primary cancer, of which 24 lesions were proved to be a second primary cancer, seven were clinically unexpected metastases, and 14 lesions were benign. Therefore, sensitivity and positive predictive value of FDG PET/CT in detecting a second primary cancer or an unexpected metastasis were 91% (31 of 34) and 69% (31 of 45), respectively. In contrast, CSW could not identify 16 second primary cancers and one metastatic lesion.

CONCLUSION: FDG PET/CT at the time of the initial staging is useful for screening a second primary cancer with a high sensitivity. An additional diagnostic work-up is essential when abnormal findings, which are indicative of a second primary cancer, are obtained on PET/CT images to rule out the presence of either a second primary cancer or an unexpected metastasis.

	INTRODUCTION

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The emergence of a second primary cancer is one of the important prognostic factors in cancer patients.^1,2 A second primary cancer is the leading cause of treatment failure and death in patients with early-stage head and neck squamous cell carcinomas.³ Cancer survivors have approximately twice the chance of developing a new primary cancer than a cancer-free individual of the same age and sex.^2,4 Furthermore, second primary cancers frequently arise in unfavorable sites, such as the esophagus, which has a poor prognosis, as well as in previously treated or unexpected areas where an early diagnosis is difficult.^1-4 In this context, the early detection of a second primary cancer is essential to reduce the morbidity and mortality associated with second tumors, particularly in patients without the symptoms that are indicative of a second primary cancer.^1,2 Conventional radiologic methods such as simple radiography and computed tomography (CT) are not suitable because of the relatively low sensitivity and limited field of coverage.^5,6 Therefore, a new diagnostic method is needed to efficiently screen a second primary cancer.

Whole-body positron emission tomography (PET) using [¹⁸F] fluorodeoxyglucose (FDG) has shown good results for detecting, staging, and evaluating the prognosis of many tumors.^7-9 In head and neck cancer, which is one of the major risk factors for a second primary cancer, FDG PET showed good results in detecting a second primary cancer compared with radiologic methods.^5,6 However, there are few reports on the use of FDG PET for the detection of a second primary malignancy in other types of cancer. Furthermore, conventional PET has some limitations in localizing an anatomic lesion and differentiating the pathologic from the physiologic FDG uptake.^10,11 A recently developed integrated PET/CT, which can provide both the metabolic and anatomic information of a cancer, has been shown to have better accuracy in tumor staging than either CT or conventional PET.^11,12

This prospective study evaluated the value of integrated FDG PET/CT in detecting a second primary cancer at the time of the initial tumor staging and compared the results with those obtained using a conventional staging work-up.

	METHODS

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Patients
From May 2003 to April 2004, 1,666 consecutive patients underwent a whole-body FDG PET/CT at our institute. The inclusion criteria for this study were as follows. First, the primary tumor had to show proven malignancy by histopathology. Second, FDG PET/CT had to be performed for the initial tumor staging before treatment within 1 month of the conventional staging work-up. Third, no patient had a medical history of cancer. A total of 555 patients were eligible for this prospective study. The conventional staging work-up was performed on all patients according to the clinical needs, as well as the location and the cell type of the primary tumor. For example, in non–small-cell lung cancer, the conventional staging work-up included a physical examination, chest radiography, bone scintigraphy, bronchoscopy, and chest CT. For esophageal cancer, a physical examination, chest radiography, esophagogastroduodenoscopy, endoscopic ultrasound, abdominal ultrasonography, and chest CT were performed at our institute. The protocol of the conventional staging work-up is described in detail elsewhere.⁷ The Ethics Review Committee of our institute approved the study protocol.

PET/CT Imaging
All of the patients fasted for at least 6 hours before the PET study. The PET/CT scan was performed using a GE Discovery LS PET/CT scanner (General Electric, Milwaukee, WI). The whole-body CT scanning was performed using a continuous spiral technique on an eight-slice helical CT with a gantry rotation speed of 0.8 seconds. The CT scan data were collected with 40 to 80 mAs adjusted to the patients' body weight, a 140 keV, a 5-mm section width, and a table feed of 5 mm per rotation. After the CT scan, an emission scan was performed from the thigh to the head for 5 minutes per frame 45 minutes after the intravenous injection of 370 MBq FDG. The attenuation-corrected PET images using the CT data were reconstructed using an ordered subsets expectation maximization algorithm (28 subsets, two iterations). Commercial software (eNTEGRA; Elgems, Haifa, Israel) was used to coregister the separate CT and PET scan data accurately. The standardized uptake values were acquired using the attenuation-corrected images, the amount of the injected FDG, the body weight of each patient, and the cross-calibration factors between PET and the dose calibrator.

Data Analysis
The CT image, PET image, and the fused PET/CT images were reviewed by two nuclear medicine physicians and one radiologist, who had access to the relevant clinical information. Initially, the nuclear medicine physicians reviewed the PET images without the assistance of the CT images to correct the attenuation. The physicians then identified those lesions with an abnormal FDG uptake. A radiologist reviewed the CT and fused PET/CT images, and determined the precise anatomic location and the presence of a morphologic alteration on the CT images of each lesion with an abnormal FDG uptake. When an abnormal focal FDG uptake was identified on an unusual organ for a metastasis considering the CT findings and the biologic behavior of the alleged primary index tumor, the physician in charge was notified of this finding, and an additional diagnostic work-up or pathologic confirmation was performed. All lymph nodes with an abnormal FDG uptake were considered to be metastatic or reactive nodes. With lung and liver lesions, where metastases frequently occur, only a single nodule or a mass with increased FDG uptake was considered to be suggestive of a second primary cancer. Multiple nodules or masses with increased FDG uptake were considered to be metastases. In any organ such as lymphoid tissue and intestines where a physiologic or nonspecific FDG can occur, only the combined metabolic and anatomic alteration was considered to be an abnormal focal FDG uptake that was indicative of second primary cancer.^9,10

An additional diagnostic work-up or pathologic confirmation was also performed when the conventional staging work-up gave abnormal findings indicative of a second primary cancer.

When the cell type between the primary and suspected second primary cancers was identical, a determination of a metastasis or second primary cancer was made based on findings from a tumor board, which considered the comparative histologic findings, the biologic behavior of the primary tumor, and the radiologic appearance. The clinical or pathologic stage was determined according to the TNM system.¹³

Statistical Analysis
The statistical differences were analyzed using Fisher's exact test for a nonpaired variable and McNemar test for a paired variable. The numeric data were expressed as a mean ± standard deviation. A P value less than .05 was considered significant.

	RESULTS

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An additional evaluation was not performed in eight patients with an abnormal FDG uptake indicative of a second primary cancer (two in nasopharynx, two in vocal cord, two in thyroid, one in esophagus, one in colon) because of extensive stage IV disease (four with lung cancer, one with esophageal cancer) and the patients' refusal to undergo additional tests and treatment (three with lung cancer). Those patients were excluded from additional analyses. Table 1 shows the demographics and clinical characteristics of the 547 remaining patients.

View larger version (59K): [in this window] [in a new window]   Fig 1. [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) using PET/computed tomography (CT) image of a 68-year-old male patient with an esophageal squamous cell carcinoma showing a hypermetabolic mass in the sigmoid colon (maximum standardized uptake value, 13.7) along with focally increased uptake in the lower thoracic esophagus, which was identified by an endoscopic biopsy to be an adenocarcinoma.

The mean clinical follow-up duration after the diagnosis of the primary index tumor was 9.2 ± 5.2 months. During the clinical follow-up, no second primary cancers were found except for one patient with an early gastric cancer, which was detected incidentally during an endoscopic examination.

	DISCUSSION

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These results demonstrated that integrated whole-body FDG PET/CT is a useful tool for screening for a second primary cancer in cancer patients at the time of the initial tumor staging. The high sensitivity of 91% (100% when gastric cancers are excluded) and positive predictive value of 69% for detecting a second primary cancer or an unexpected metastasis highlight the use of FDG PET/CT as a tool for screening a second primary cancer. The relative high positive predictive value of PET/CT suggests that an additional diagnostic work-up is essential to exclude the possibility of a second primary cancer or an unexpected metastasis when an abnormal finding indicative of a second primary cancer was obtained on FDG PET/CT. Most second primary cancers detected by PET/CT (83.3%; 20 of 24) were in early stage (I or II), which provides a better opportunity for cure. During the follow-up, no second primary cancers were found except for one patient with an early gastric cancer. This emphasizes the value of FDG PET/CT in detecting a second primary cancer.

All three false-negative results on FDG PET were early gastric cancers that were only detected by endoscopy, which is part of conventional staging work-up only in esophageal and gastric cancers. It is difficult to differentiate the physiologic uptake or benign gastric lesions from early gastric cancers using FDG PET, particularly in small lesions.¹⁴ Our results also supported that esophagogastroduodenoscopy could not be replaced by PET/CT for screening gastric malignancies. The thyroid was the most common false-positive site for detecting a second primary cancer on PET/CT. Previous studies also showed that the positive predictive value for a malignancy was less than 50% when the abnormal focal FDG uptake was found incidentally on the thyroid.^15,16 When thyroid lesions were excluded, the positive predictive value of PET/CT for detecting a second primary cancer or unexpected metastasis improved to 81% (26 of 32). Conventional staging work-up showed a poor sensitivity (only 50%) in detecting a second primary tumor or an unexpected metastasis, which means that the conventional staging work-up is unsuitable for screening a second primary cancer.

In this study, the overall prevalence of a second primary cancer was 5%. In particular, the overall prevalence of a second primary cancer was significantly higher in chronic smokers (6.5%) than in nonsmokers (2.7%). This indicates that chronic smoking is an important risk factor for the development of a second primary cancer, which concurs with previous studies.² The prevalence of a second primary cancer was highest in esophageal cancer (12%), which was different from results of a previous study.² This might be the result of geographic variations. The incidence of esophageal cancer was reported to be higher in those residing in Central Russia and East Asia, and most of the esophageal cancers are squamous cell carcinomas. A recent Japanese study reported a high 10-year cumulative risk of developing a second primary malignancy (35%) in patients with treated esophageal cancer.¹⁷ A second primary cancer was also relatively common in genitourinary cancer (7.7%) and head and neck cancer (7%), which is similar to that reported elsewhere.^1-3 This suggests that FDG PET/CT can be used for not only the initial tumor staging, but for screening a second primary cancer in these patients.

It is well known that integrated PET/CT, which is performed by image fusion through hardware, has many advantages, such as a single scanning session with convenience for both the patient and physician; accurately aligned anatomic and functional images with an accurate localization and the identification of nonpathologic, abnormal uptake lesions; and the easy accessibility for making surgical plans or image-guided surgery with confidence, even for inexperienced surgeons.^11,18 In this study, the FDG PET/CT fusion images provided additional information in 22 (48.9%) of the 45 lesions with an abnormal focal FDG uptake that was indicative of a second primary malignancy with an accurate anatomic localization and concurrent anatomic abnormality. This suggests that PET/CT is superior to PET in screening for a second primary cancer.

In conclusion, FDG PET/CT at the time of the initial tumor staging is useful for screening a second primary cancer with a high sensitivity and positive predictive value. An additional diagnostic work-up is essential to rule out the presence of a second primary cancer or an unexpected metastasis when abnormal findings indicative of a second primary cancer are found on the PET/CT images. PET/CT is more suited to detecting a second primary tumor than conventional PET because the combined method provides both the metabolic and anatomic information. In addition, most second primary cancers were detected in the early stage, which might have major favorable consequences for the patients' prognosis and survival. A longer follow-up with a larger number of patients will be needed to confirm this relationship.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Presented in part at the Annual Meeting of the Society of Nuclear Medicine, Philadelphia, PA, June 19-23, 2004.

Supported by Grant No. 02-PJ3-PG6-EV06-0002 from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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1. Leon X, Ferlito A, Myer CM III, et al: Second primary tumors in head and neck cancer patients. Acta Otolaryngol 122:765-778, 2002[Medline]

2. Rheingold SR, Neugut AI, Meadows AT: Secondary cancers: Incidence, risk factors, and management, in Kufe DW, Pollock RE, Weichselbaum RR, et al (ed): Cancer Medicine (ed 6). Hamilton, Ontario, BC Decker, 2003, pp 2623-2631

3. Lippman SM, Hong WK: Second malignant tumors in head and neck squamous cell carcinoma: The overshadowing threat for patients with early-stage disease. Int J Radiat Oncol Biol Phys 17:691-694, 1989[Medline]

4. Dong C, Hemminki K: Second primary neoplasms in 633,964 cancer patients in Sweden, 1958-1996. Int J Cancer 93:155-161, 2001[CrossRef][Medline]

5. Stokkel MP, Moons KG, ten Broek FW, et al: [¹⁸F]-fluorodeoxyglucose dual-head positron emission tomography as a procedure for detecting simultaneous primary tumors in cases of head and neck cancer. Cancer 86:2370-2377, 1999[CrossRef][Medline]

6. Stokkel MP, ten Broek FW, Hordijk GJ, et al: Preoperative evaluation of patients with primary head and neck cancer using dual-head [¹⁸F]-fluorodeoxyglucose positron emission tomography. Ann Surg 231:229-234, 2000[CrossRef][Medline]

7. Choi JY, Lee KH, Shim YM, et al: Improved detection of individual nodal involvement in squamous cell carcinoma of the esophagus by FDG PET. J Nucl Med 41:808-815, 2000[Abstract/Free Full Text]

8. Gambhir SS, Czernin J, Schwimmer J, et al: A tabulated summary of the FDG PET literature. J Nucl Med 42:1S-93S, 2001 (suppl 5)

9. Choi JY, Jang HJ, Shim YM, at al: [¹⁸F]-FDG PET in patients with esophageal squamous sell carcinoma undergoing curative surgery: Prognostic implications. J Nucl Med 45:1843-1850, 2004

10. Bar-Shalom R, Yefremov N, Guralnik L, et al: Clinical performance of PET/CT in evaluation of cancer: Additional value for diagnostic imaging and patient management. J Nucl Med 44:1200-1209, 2003[Abstract/Free Full Text]

11. Wahl RL: Why nearly all PET of abdominal and pelvic cancers will be performed as PET/CT. J Nucl Med 45: 82S-95S, 2004 (suppl 1)

12. Antoch G, Saoudi N, Kuehl H, et al: Accuracy of whole-body dual-modality fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT) for tumor staging in solid tumors: Comparison with CT and PET. J Clin Oncol 22:4357-4368, 2004[Abstract/Free Full Text]

13. Greene FL, Page DL, Fleming ID, et al: AJCC Cancer Staging Manual (ed 6). New York, NY, Springer-Verlag, 2002

14. Mochiki E, Kuwano H, Katoh H, et al: Evaluation of [¹⁸F]-2-deoxy-2-fluoro-D-glucose positron emission tomography for gastric cancer. World J Surg 28:247-253, 2004[CrossRef][Medline]

15. Cohen MS, Arslan N, Dehdashti F, et al: Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucose-positron emission tomography. Surgery 130:941-946, 2001[CrossRef][Medline]

16. Kang KW, Kim SK, Kang HS, et al: Prevalence and risk of cancer of focal thyroid incidentaloma identified by [¹⁸F]-fluorodeoxyglucose positron emission tomography for metastasis evaluation and cancer screening in healthy subjects. J Clin Endocrinol Metab 88:4100-4104, 2003[Abstract/Free Full Text]

17. Matsubara T, Yamada K, Nakagawa A: Risk of second primary malignancy after esophagectomy for squamous cell carcinoma of the thoracic esophagus. J Clin Oncol 21:4336-4341, 2003

18. Townsend DW, Carney J, Yap JT, et al: PET/CT today and tomorrow. J Nucl Med 45:4S-14S, 2004 (suppl 1)

Submitted February 1, 2005; accepted July 21, 2005.

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