Journal of the National Cancer Institute Advance Access originally published online on May 13, 2008
JNCI Journal of the National Cancer Institute 2008 100(10):688-689; doi:10.1093/jnci/djn149
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© The Author 2008. Published by Oxford University Press.
EDITORIAL |
FDG-PET Staging of Head and Neck Cancer—Can Improved Imaging Lead to Improved Treatment?
Affiliation of authors: Departments of Radiation Oncology (DLS), Experimental Diagnostic Imaging (DLS), Nuclear Medicine (HAM), and Head and Neck Surgery (RSW), The University of Texas M. D. Anderson Cancer Center, Houston, TX
Correspondence to: David L. Schwartz, MD, Department of Radiation Oncology, Unit 97, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: docdls{at}mdanderson.org).
Head and neck cancer levies a steep toll from those it afflicts, particularly through treatment-associated toxicity. Tangible improvements in tissue sparing, supportive care, and recuperative strategies have been made. Nonetheless, combined modality strategies favored for locally advanced disease continue to demand substantial cosmetic, nutritional, and functional sacrifices in exchange for improved survival. The way to best limit such morbidity is to tailor treatment to the exact location and severity of disease. If the tumor can be reliably localized, bystander tissues appropriately excluded from operative and radiation fields, and lower risk patients safely triaged away from cytotoxic chemotherapy, then the up-front and longitudinal costs of head and neck cancer treatment can be tangibly reduced without conceding efficacy.
In this spirit, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging has gradually become part of the routine management of head and neck cancer over the past decade. FDG-PET has been touted to provide benefit for a spectrum of indications, including up-front locoregional and whole-body staging, geographic delineation of tumor for radiotherapy planning or surgical neck management, detection of disease response to nonsurgical therapy (ie, chemotherapy, radiation, or chemoradiation), identification of occult primary disease, and posttreatment surveillance and restaging. These claims have been made despite a conspicuous absence of supporting data from randomized studies. Results from cohort studies have supported many of these indications, and the sheer number of such reports certainly influenced the decision of Centers for Medicare and Medicaid Services (CMS) to approve reimbursement for FDG-PET imaging for diagnosis, staging, and posttreatment restaging of head and neck cancer (1).
In this issue of the Journal, Kyzas et al. (2) present the first formal meta-analysis available of institutional data documenting the ability of FDG-PET to accurately stage cervical neck nodal basins before locoregional treatment. The authors selected 32 retrospective and prospective studies from the international literature encompassing 1236 cases that could be analyzed in aggregate for diagnostic accuracy via confirmatory neck dissection pathology. Two-thirds of these series enrolled mixed populations of clinically node-negative (N0) and node-positive patients, and seven specifically studied patients with clinically N0 necks. The vast majority of series (and all dated before 2005) used single-modality PET scanners rather than combined PET and computer tomography (PET/CT). Analysis of this selected dataset demonstrated FDG-PET to be a sensitive (79%, 95% confidence interval [CI] = 72% to 85%) and specific (86%, 95% CI = 83% to 89%) staging technique for this indication. In head-to-head comparisons with "competing" modalities, FDG-PET provided incremental, yet clinically meaningful improvements in neck staging accuracy. A notable exception to this rule was ultrasound-guided fine-needle aspiration, which not surprisingly, given that it is a mixed imaging-tissue diagnostic procedure most frequently performed by specialized diagnosticians at referral centers, appeared to outperform PET's sensitivity. Another noteworthy finding was that FDG-PET could not improve detection of occult adenopathy in clinically N0 patients. This result confirms the already commonly accepted notion that FDG-PET alone fails to offer clinicians suitable guidance to defer elective nodal dissection in the clinically N0 patient. One cannot single out PET for this shortcoming; 50% sensitivity is comparable to the higher range of what is reported for ultrasound-guided fine-needle aspiration or CT (3,4).
At face value, the results of this meta-analysis formalize what the majority of head and neck FDG-PET imaging reports have suggested over the past decade. Yet, real-world benefits resulting from incremental neck staging improvement provided by FDG-PET remain in the eye of the beholder. Some concur with the interpretation of Kyzas et al. (2) of the literature that FDG-PET offers "added value" over other modalities (5). Others come to a less sanguine conclusion (6), claiming FDG-PET to be "useless" for improving on CT alone. And although ample evidence exists to show that FDG-PET can refine treatment for a sizable proportion (perhaps 
30%) of patients (7,8), the validity and ultimate survival impact of such PET-mediated alterations remain unsubstantiated. We will not referee this debate to a resolution here, but we can say that up-front staging would be expected to be one of FDG-PET imaging's stronger suits. PET detects physiological perturbations within biologic systems with exquisite sensitivity. Differential glucose uptake by tumor cells (ie, the so-called "Warburg effect") is a fundamental hallmark of most cancer phenotypes. PET is not hamstrung by the formal size criteria (typically 8–15 mm) required to identify nonnecrotic nodal metastases by structural imaging. Registered imaging with combined PET/CT scanners may further improve on incremental staging gains won with FDG-PET alone (9), perhaps to the point at which sentinel node biopsies or carefully selected radiation dose de-escalation to FDG-nonavid regions of the neck can become generally accepted. Nonetheless, the limitations inherent to the physics and image reconstruction methods that localize labeled tumor cells predict that PET would be of limited use for detecting small disease rests less than 5 mm in diameter, as would be expected in occult positive nodes in the clinically negative neck. We remain at an impasse with any single diagnostic maneuver in this clinical situation.
And this brings into focus the inadequacy of a "beauty pageant" approach to assessing the relative worth of specific imaging modalities. Side-by-side comparisons of technologies, although straightforward and important for initial validation, have less relevance to mature deployment in the clinic, where providers tend to interpret diagnostic results via Bayesian approaches that modify interpretation in accordance with prior diagnostic findings. Different diagnostic techniques work best when they are used to complement one another, thus the motivation to house PET and CT (and more recently magnetic resonance imaging [MRI]) instruments within combined units. Recent prospective series in early–intermediate T stage oral cavity and oropharyngeal cancer patients serve to reinforce the idea that FDG-PET can potentially guide more appropriate management of clinically N0 patients but only when directly correlated with CT and sentinel node biopsy (10) or (less ideally) with CT/MRI findings (11). Thus, more important than asking whether FDG-PET can confirm N0 status on its own is whether it can provide definitive guidance for indeterminate cervical adenopathy that is distinct from metastatic nodes already documented by CT. This issue could impact surgical and radiotherapy management yet was not directly addressed by the literature analyzed by Kyzas et al. (2).
And there are other inherent limitations to the dataset analyzed by Kyzas et al. (2). Outcomes were gathered across a wide spectrum of head and neck disease sites, stages, and treating institutions, as evidenced by the authors’ supplementary data. The last of these variables is of particular importance to PET imaging, given the potential confounding influence of differing image acquisition protocols, instrumentation, and image interpretation methods (12). Although the sensitivity for detecting utility with FDG-PET may be gained with the authors’ meta-analytic approach, specificity for eliciting its most appropriate indications is lost. Fortunately, we should note that the Radiation Therapy Oncology Group (RTOG) and American College of Radiology Imaging Network (ACRIN) are evaluating many such issues in the multi-institutional setting via a formal FDG-PET/CT imaging study incorporated within the current RTOG 0522 phase III trial examining combined chemoradiotherapy for locally advanced head and neck cancer (13). ACRIN is also coordinating case collection for the National Oncologic PET Registry (14). The Registry serves as a mechanism for CMS reimbursement to providers for cancer-related indications awaiting approval (including FDG-PET treatment monitoring in head and neck disease) while prospectively evaluating the impact of FDG-PET on clinical management.
In summary, because head and neck cancer is approached with purposeful consideration of regionalized management of primary tumor and cervical neck nodes, it is an ideal candidate site for incorporation of imaging advances that improve disease localization, such as FDG-PET. Nonetheless, head and neck lags behind other disease sites with regard to multi-institutional randomized data that discretely define the clinically relevant capabilities of FDG-PET (15–17) or permit formal incorporation of FDG-PET into treatment pathways (18). PET is a resource-intensive technology that has the potential to convolute and misdirect management if not leveraged to its strengths. Although Kyzas et al. (2) are to be commended for sustaining momentum toward implementing FDG-PET on behalf of head and neck cancer patients, prospective data remain a critical necessity to translate imaging improvements with FDG-PET into proven treatment improvements.
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