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Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 599-604 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.8760 [18F]Fluorodeoxyglucose Positron Emission Tomography Is More Sensitive Than Skeletal Scintigraphy for Detecting Bone Metastasis in Endemic Nasopharyngeal Carcinoma at Initial StagingFrom the Department of Nuclear Medicine and Molecular Imaging Center; Department of Radiation Oncology, Division of Hematology/Oncology; Department of Internal Medicine, Section of Head and Neck Surgery; Department of Otorhinolaryngology; and Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan Address reprint requests to and correspondence to Tzu-Chen Yen, MD, PhD, Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, 199 Dunhua N Rd, Taipei 10507, Taiwan; e-mail: yen1110{at}adm.cgmh.org.tw
PURPOSE: Bone metastasis occurs frequently in patients with endemic nasopharyngeal carcinoma (NPC). The main objective of this study is to evaluate positron emission tomography (PET) using fluorine-18–labeled fluorodeoxyglucose ([18F]FDG) and conventional skeletal scintigraphy (SS) for detecting bone metastasis at initial staging. Auxiliary objectives are to identify risk factors for bone metastasis and features associated with poor survival in patients with bone metastasis. PATIENTS AND METHODS: Patients with endemic NPC before initiation of treatment were enrolled. PET and SS were performed at initial staging and compared using McNemar's paired-sample test. Bone metastasis was considered to be present if there was any reliable evidence identified within 1 year after primary diagnosis. Multiple logistic regression and Cox's proportional hazards models were used for auxiliary objectives. RESULTS: Thirty (15%) of 202 eligible patients were found to have bone metastasis. [18F]FDG PET was found to be more sensitive than SS in the patient-based analysis (P = .006) and in the region-based analysis at the spine (P = .001). Advanced N stage was the only significant risk factor (P < .0001), and the coexistence of hepatic metastasis was a prognosticator of poor survival (P = .017). The survival was not significantly better for patients with bone metastasis undetected at primary staging than for those with initially detectable bone metastasis (P = .620). CONCLUSION: [18F]FDG PET is more sensitive than SS for detecting bone metastasis in endemic NPC at initial staging, whereas SS can be considered as supplementary in this setting.
Nonkeratinizing nasopharyngeal carcinoma (NPC), endemic in southern China, Southeast Asia, North Africa, and Alaska, is an epithelial neoplasm with WHO histologic classification of type II (differentiated nonkeratinizing carcinoma) or type III (undifferentiated carcinoma).1,2 It differs from squamous cell carcinomas of the head and neck in etiology, natural history, and response to treatment.3 Endemic NPC has a greater tendency for early locoregional spread, whereas its higher sensitivity to radiotherapy and chemotherapy produces a better prognosis. Overt distant metastasis has been detected in up to 11% of NPC patients at initial diagnosis, and the skeleton is the most frequent site involved in 70% to 80% of patients with distant metastasis.4 In contrast, pulmonary metastasis is the most frequent in squamous cell carcinomas of the head and neck, accounting for two thirds of distant metastasis.5 Early detection of distant metastasis is essential for precise staging, optimal management, and accurate comparison between different therapeutic protocols in patients with advanced disease. Conventional skeletal scintigraphy (SS) using technetium-99m–labeled diphosphonates is still the most frequently used method for detecting bone metastasis because of its wide availability and low cost. However, early bone metastasis, especially when the majority of tumor cells are confined in the bone marrow, frequently is missed by SS.6 Differentiation between malignant and benign lesions by SS is also problematic, even with experienced nuclear physicians. A substantial portion of patients with advanced NPC will develop distant metastasis after treatment, with a median time of less than 1 year.7 In a study performed by Caglar et al,8 26 (15%) of 171 NPC patients without evidence of distant metastasis at initial staging developed bone metastasis on follow-up SS, with a median time of 10.5 months from primary diagnosis. The presence of subclinical metastasis undetected by SS at initial staging was presumed to explain these results. Apparently, more sensitive examinations that can detect early bone metastasis are needed. Positron emission tomography (PET) using [18F]fluorodeoxyglucose ([18F]FDG) has become popular in recent years due to its unique capability to image metabolically active lesions. It is indicated in the diagnosis and staging of head and neck cancers. For evaluating NPC patients at initial presentation, [18F]FDG PET is effective not only in identifying locoregional lesions but also in revealing unsuspected distant metastases.9,10 Estimates of the sensitivity of [18F]FDG PET for detecting bone metastasis in cancers range from 62% to 100%.11 To the best of our knowledge, no related study for NPC has been performed. The main objective of this study was to evaluate prospectively [18F]FDG PET and SS for detecting bone metastasis in endemic NPC patients at initial staging; the auxiliary objectives were to identify the risk factors for bone metastasis and the features associated with poor survival in the patients with bone metastasis.
Patients and Study Design Histologically proven NPC patients without previous malignancy were enrolled before primary treatment. Patients with tumor histology other than WHO types II or III were excluded. The current study, approved by the Institutional Review Board, required written informed consents from the enrolled patients. Imaging studies including magnetic resonance imaging (MRI) of the head and neck, chest x-ray, hepatic ultrasonography, whole-body SS, and [18F]FDG PET were routinely performed within 2 weeks after enrollment. The T and N staging for each patient, according to the American Joint Committee on Cancer TNM staging system published in 2002, was determined by combining clinical, MRI, and PET findings and biopsy or aspiration results. After primary staging, patients without overt distant metastasis were treated with concurrent chemoradiotherapy or radiotherapy. Patients with clinical characteristics suggestive of distant metastasis would receive additional studies such as computed tomography (CT), MRI, and biopsy or aspiration at the sites in question. Systemic chemotherapy was initiated if the presence of distant metastasis had been confirmed. The first imaging follow-up including head and neck MRI and [18F]FDG PET was scheduled at 3 months after completion of radiotherapy or 1 month after completion of chemotherapy. If we estimate from the 11% rate of overt distant metastasis at initial staging, 75% of which involved the skeleton, and presence of subclinical bone metastasis in 15% of the remaining patients, the prevalence of bone metastasis and the sensitivity of SS at primary staging should be approximately 22% and 38%, respectively. Assuming a modest sensitivity of 60% for detecting bone metastasis by [18F]FDG PET, a discordant rate of 25% between the results of [18F]FDG PET and SS, a significance level of .05 with a power of .90, and using McNemar's paired-sample test for statistical comparison, the required number of patients should be more than 155.
18F-FDG PET Imaging
SS
Image Interpretation
Determination of the Presence of Bone Metastasis and Other Distant Metastasis
Follow-Up of Patient Status
Statistical and Survival Analyses
Patient Demographics Two hundred nine patients were enrolled between April 2002 and June 2004. Excluding four patients who had dropped out of the study before the 1-year follow-up, two patients with histology of WHO type I, and one patient with adenoid cystic carcinoma of the nasopharynx, a total of 202 patients were eligible for analysis. Baseline demographic and disease characteristics are listed in Table 1. The median age was 49.6 years at primary diagnosis and the male-to-female ratio was 2.7.
Detection of Bone Metastasis by [18F]FDG PET and SS Thirty patients (15%) were found to have bone metastasis. At initial staging, 21 patients (70%) were detected by [18F]FDG PET and 11 patients (37%) were detected by SS. Eleven patients with bone metastasis were detected by [18F]FDG PET rather than SS, whereas one patient with a solitary rib metastasis confirmed later by biopsy was detected by SS only. Results of the patient-based and region-based analyses are listed in Table 2. [18F]FDG PET was significantly more sensitive and accurate than SS in the patient-based analysis and in the region-based analysis at the spine. Figure 1 shows an exemplary case with positive [18F]FDG PET and negative SS findings. Noticeable bone lesions on x-ray or CT images were found in eight of the 30 patients, and all revealed the radiographic characteristic of mixed osteolysis and osteoblastosis.
Risk Factors for Distant Metastasis Thirty-seven patients (18%) were noted to have distant metastasis. The statistical analyses for probable risk factors are presented in Table 1, and the N stage was the only significant factor (P < .0001). None of the patients with stage N0 had distant metastasis, whereas one (2%), three (4%), four (36%), and 29 (71%) of the patients with stage N1, N2, N3a, and N3b had distant metastasis, respectively. Similar comparisons for patients with bone metastasis and patients with distant metastasis not involving the skeleton are listed in Table 3, and no significant difference was identified.
Follow-Up of Patient Status and Survival Analysis Of those without evidence of distant metastasis, there were 153 NED patients at a median follow-up of 19 months; seven AWD patients, three DWD patients, and two patients died as a result of other causes without evidence of disease. Excluding five patients who had not completed the primary therapy and three patients with residual or persistent disease after treatment, there were two patients with relapse after initial remission. One patient had locoregional recurrence identified at 19 months, whereas the other had both locoregional recurrence and distant metastasis identified at 16 months. Additional follow-up is needed to determine whether patients will develop distant metastasis without locoregional failure. Of those with distant metastasis, there were 21 DWD patients, 15 AWD patients, and one NED patient. The median survival for patients with bone metastasis was 20 months. The analysis of probable prognosticators of poor survival is listed in Table 4, and only the coexistence of hepatic metastasis was noted to be significant (P = .017). Survival curves for patients with or without the coexistence of hepatic metastasis and for patients with bone metastasis detected at or after primary staging are illustrated in Figure 2.
Reviews and studies of [18F]FDG PET for detecting bone metastasis have been reported for breast cancer, lung cancer, and prostate cancer.12-14 [18F]FDG PET is generally more accurate than SS, with the exception for prostate cancer in which the bone metastases are predominantly osteoblastic. In the current study, [18F]FDG PET was more sensitive and accurate than SS, especially for lesions in the vertebral spine. Although the trend was statistically insignificant, [18F]FDG PET also showed the same trend for the pelvic bones. For the thoracic cage, there seemed to be an opposite, albeit small and insignificant, inclination for SS to be more sensitive. In our experience, [18F]FDG PET seems to be less sensitive for detecting rib metastases, presumably because of the smaller marrow space that might confine the number of proliferating tumor cells at the earlier phase of metastasis. In contrast, the osteoblastic reaction in the ribs seems to be detected easily by SS. A previous study revealed SS to be more sensitive for lesions in the skull and thorax rather than those in the spine and pelvis.15 For the appendix, [18F]FDG PET did not seem to be less sensitive than SS even the lower extremities below the upper thighs have not been covered in the imaging range of [18F]FDG PET studies. This might be explained by the predilection of bone metastasis for proximal femora and humeri in the extremities and their larger marrow spaces. Bone metastases traditionally have been designated as osteolytic or osteoblastic, although these two patterns represent the extremes in a continuum of the malfunctioning bone remodeling process.16 Cook et al17 observed that [18F]FDG PET was more sensitive for detecting osteolytic/mixed than osteoblastic lesions in breast cancer. There are usually more tumor cells with a higher glycolytic rate in osteolytic lesions, and tumor hypoxia resulting in enhanced glycolysis has also been proposed as a potential factor. Previous and current studies showed that the majority of bone metastases in NPC were osteolytic/mixed, and this could account for the superiority of [18F]FDG PET in our study.18,19 The only significant risk factor for distant metastasis is advanced N stage, especially when the lymphatic metastases extend to the supraclavicular region (N3b). This may lead to the assumption that tumor cells responsible for distant metastasis originate in the lymph nodes rather than from the primary tumor. Additional genotypic and phenotypic studies are required for validation.20 Newly diagnosed metastases during the first year after primary diagnosis were assumed to be present subclinically at initial staging. This hypothesis seems appropriate given that no patient with locoregional control has yet developed distant metastasis after the first year. Other studies using SS for follow-up had detected distant bone metastasis without evidence of locoregional failure after the first year, but this might be accounted for by either the insensitivity of SS for detecting early bone metastasis or the missed detection of locoregional failure. We believe some disseminated tumor cells in the bone marrow may remain dormant and viable after primary therapy, and they have the potential to reactivate, but this kind of relapse probably is infrequent and late. Concurrent hepatic metastasis was found to be a poor prognosticator of survival in patients with bone metastasis. This finding is consistent with previous studies showing hepatic metastasis as a poor prognosticator in NPC patients with distant metastasis.21,22 In contrast, more favorable survival has been demonstrated in patients with distant metastases confined to the lungs or mediastinal/hilar lymph nodes.23,24 Interestingly, the survival was not significantly better for patients with bone metastasis undetected at primary staging than for those with initially detectable bone metastasis. This supports the hypothesis that subclinical bone or bone marrow metastasis, although undetectable by PET and SS, might be present at initial staging. It also suggests that concurrent chemoradiotherapy is not more effective than systemic chemotherapy alone for these patients. We regarded equivocal findings on PET and SS to be negative. Assigning equivocal findings to be positive would result in an increased sensitivity and a decreased specificity. Given that a false upstaging to M1 would change a patient's treatment from a curative intent to palliation, it is appropriate to remain conservative when interpreting these imaging studies. We observed a substantial portion of patients with mildly, diffusely increased FDG activity in the bone marrow at initial staging. Bone marrow stimulation agents, such as colony-stimulating factors, can induce strong FDG avidity in the bone marrow25; however, these agents were not used in our study population. Benign marrow stimulation due to anemia, immunologic response, or other chronic conditions may explain this finding.26 However, we speculated whether disseminated tumor cells or preangiogenic micrometastases in the bone marrow might show a similar picture.27 Disseminated tumor cells in the bone marrow have been shown to be present in the early stages of different cancers with prognostic significance.28-30 Little related research for the NPC population has been performed. The process by which disseminated tumor cells develop into bone metastasis is vital in the pursuit of prevention and treatment of bone metastasis.16,31 Newer preventive or therapeutic strategies, such as the use of bisphosphonates, may be proven beneficial in the near future. Although still not widely available, whole-body MRI was demonstrated to be sensitive for detecting bone marrow metastasis.32 However, the study by Daldrup-Link et al33 suggests that [18F]FDG PET is more sensitive than MRI. Because PET or combined PET-CT using [18F]FDG is indicated at the primary staging of NPC, MRI and SS for detecting bone metastasis can be considered as supplementary. PET or PET-CT using [18F]-fluoride was shown to be highly sensitive for malignant bone disease and might have complementary values to [18F]FDG studies.34,35 Additional investigations are well warranted.
The authors indicated no potential conflicts of interest.
Supported by Grant No. CMRPG32042 from the Chang Gung Memorial Hospital and University, Taipei, Taiwan. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Kwan WH, Teo PML, Chow LTC, et al: Nasopharyngeal carcinoma with metastatic disease to mediastinal and hilar lymph nodes: An indication for more aggressive treatment. Clin Oncol (R Coll Radiol) 8:55-58, 1996[Medline] 25. Sugawara Y, Fisher SJ, Zasadny KR, et al: Preclinical and clinical studies of bone marrow uptake of fluorine-18-fluorodeoxyglucose with or without granulocyte colony-stimulating factor during chemotherapy. J Clin Oncol 16:173-180, 1998 26. Vande Berg BC, Lecouvet FE, Galant C, et al: Normal variants and frequent marrow alterations that simulate bone marrow lesions at MR imaging. Radiol Clin North Am 43:761-770, 2005[Medline] 27. Chambers AF, Groom AC, MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563-572, 2002[CrossRef][Medline] 28. Braun S, Naume B: Circulating and disseminated tumor cells. J Clin Oncol 23:1623-1626, 2005 29. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) indicates a lesion at L4. (C) T1-weighted MR showed decreased signal intensity in L4 (
