F O C U S O N M O L E C U L A R I M A G I N G

Molecular Imaging in Radiotherapy Planning forHead and Neck Tumors

Vincent Gregoire1 and Arturo Chiti2

1Department of Radiation Oncology, Center for Molecular Imaging and Experimental Radiotherapy (IMRE), Universite Catholiquede Louvain, St-Luc University Hospital, Brussels, Belgium; and 2Department of Nuclear Medicine, Istituto Clinico Humanitas,Rozzano–Milan, Italy

Molecular imaging uses noninvasive techniques to visualizevarious biologic pathways and physiologic characteristics oftumors and normal tissues. In relation to radiation therapy, PETwith the tracer 18F-FDG offers a unique opportunity to refine thetarget volume delineation in patients with squamous cell carci-noma of the head and neck, in turn affecting dose distributionand, it is hoped, patient outcome. Even more so, in the frame-work of adaptive treatment and theragnostics, whereby dosedistribution is adapted in space and time over the typical courseof radiotherapy, molecular imaging with PET offers an elegantresearch avenue to further improve the therapeutic ratio. Suchimplementation could be of particular interest with tracers otherthan 18F-FDG, such as tracers of hypoxia and proliferation.

Key Words: PET; FDG; radiotherapy; target volume delineation;dose painting

J Nucl Med 2011; 52:331–334DOI: 10.2967/jnumed.110.075689

Molecular imaging, also referred to as biologic or func-tional imaging, uses noninvasive techniques to visualizevarious biologic pathways and physiologic characteris-tics of tumors and normal tissues. It refers mainly (but notonly) to PET and functional MRI. In clinical oncology,molecular imaging offers the unique opportunity of allow-ing earlier diagnosis and staging of disease; contributes tothe selection and delineation of optimal target volumes forradiotherapy and, to a lesser extent, surgery; assesses re-sponse early during treatment or after its completion; andhelps in the early detection of recurrence (1,2).It appears that more and more radiation oncologists are

routinely using information provided by 18F-FDG PET toselect or delineate target volumes in patients with squamouscell carcinoma of the head and neck (HNSCC). However,how do the figures for the specificity and sensitivity of 18F-FDG PET compare with those of anatomic imaging such as

CT or MRI in the diagnosis of primary tumors and meta-static lymph nodes in the neck? How does 18F-FDG PET–based delineation of primary tumor gross target volume(GTV) compare with CT- or MRI-based GTV? How doesthe use of 18F-FDG PET–based volumes modify the dosedistribution, allowing for normal tissue sparing, dose inten-sification, or dose painting? Are other tracers such as hyp-oxic or proliferation tracers of any use?

This review of state-of-the-art therapeutic managementof patients with HNSCC will present all available datajustifying the use of PET with 18F-FDG or other tracers inthese patients. Only squamous cell carcinoma of the oralcavity, oropharynx, hypopharynx, and larynx, and neckmetastasis of an occult primary, will be discussed.

18F-FDG PET FOR TARGET VOLUME SELECTION

The use of 18F-FDG PET in HNSCC has been proposed inmany studies, and several meta-analyses have tried to assessthe level of evidence for this technique in various clinicalscenarios. Although published data do not indicate a clearrole for 18F-FDG PET in HNSCC patients, technology isevolving quickly in this field and published data indicatingmerit are often from studies conducted with scanners thatcan no longer be considered the state of the art.

Indications addressed in published reports are relatedmostly to the diagnostic accuracy of PET in the detection ofan occult primary tumor in patients with cervical lymph nodemetastases. These tumors might not have been identified onclinical examination and imaging, or they might only besuspected with other diagnostic modalities. In this clinicalscenario, 18F-FDG PET is able to detect about one quarter ofoccult primaries (3), but its value over CT and MRI stillneeds to be confirmed. Besides the identification of theoccult primary tumor, the added value of PET is in thedetection of distant metastases—a use for which it has shownhigh sensitivity. Clearly, the discovery of metastatic lesionshas a great impact on patient management (4).

Several studies have been published on the assessment ofHNSCC primary tumor using PET, with reported sensitiv-ities, specificities, and accuracies of over 90% (5). None-theless, PET has not been shown to have any advantageover CT and MRI and is therefore not recommended cur-

Received Jun. 28, 2010; revision accepted Sep. 30, 2010.For correspondence or reprints contact: Vincent Gregoire, Department of

Radiation Oncology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate10, B-1200 Brussels, Belgium.E-mail: vincent.gregoire@uclouvain.beCOPYRIGHT ª 2011 by the Society of Nuclear Medicine, Inc.

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rently for routine diagnostic imaging of primary head andneck cancer. New studies using integrated state-of-the-artPET/CT scanners might change this indication.The role of PET in the identification of lymph node

metastases was the subject of a recent meta-analysis (6).Sensitivity and specificity were not significantly higher for18F-FDG PET than for ultrasound, CT, or MRI. In patientswith clinically negative neck nodes, PET sensitivity was aslow as 50%, without any advantage over conventional imag-ing techniques, particularly when compared with ultrasound-guided fine-needle aspiration cytology.Although 18F-FDG has a limited role for the primary

tumor and node staging, it is considered appropriate forthe evaluation of patients after radiation therapy or chemo-therapy with or without a clinical or imaging suspicion ofrelapsing disease (7). In this setting, particular attentionmust be paid to inflammatory changes due to radiationtherapy, which may easily lead to false-positive reports. Itis beyond the scope of this review article to extensivelydiscuss these indications and pitfalls.

18F-FDG PET FOR TARGET VOLUME DELINEATION ANDDOSE PLANNING

Accurate evaluation of the primary tumor and its exten-sions remains challenging and difficult for the radiationoncologist. This issue is crucial because the GTV representsthe volume that has the highest tumor cell density and shouldmost accurately receive the prescribed dose. GTV delinea-tion relies mainly on a comprehensive physical examinationand the use of optimal imaging modalities but also on soundclinical judgment and in-depth knowledge of head and neckanatomy and the pathways for tumor spread. The imagingmodalities currently available can offer anatomic (e.g., CTand MRI) or functional (e.g., PET) information, but allpresent limitations in spatial or contrast resolution and insensitivity and specificity. These limitations may signifi-cantly affect image interpretation and subsequent tumordelineation.In HNSCC, both GTVs and organs at risk are typically

delineated on planning CT. CT presents numerous advan-tages, including its widespread availability, acceptable cost,high spatial resolution, and intrinsic information on theelectronic density used for dose calculation. However, CTlacks contrast resolution for soft tissues and tumor extentand is sensitive to metallic artifacts, such as dental fillings,limiting its performance in assessing oropharyngeal andoral cavity tumors. The use of contrast-enhanced CT andthe availability of delineation guidelines have been shownto improve consistency between observers (8), emphasizingthe importance of image quality and guidelines for delin-eation criteria. In comparison to CT, MRI offers better soft-tissue contrast, which may improve the delineation of GTVnear the base of the skull, such as in nasopharyngeal orparanasal sinus cancers and in tongue, base-of-tongue,and floor-of-mouth tumors. However, for pharyngolaryn-

geal tumors, several studies have failed to show any addedvalue of MRI over CT in volumetrics and reproducibility,even when optimal MRI sequences with high spatial reso-lution were used (9).

Besides these anatomic imaging modalities, the use of18F-FDG PET, which provides unique information on cellu-lar function, has become increasingly popular in radiother-apy planning. In pioneering work, Daisne et al. demonstratedthat the introduction of 18F-FDG PET for the delineation ofpharyngolaryngeal squamous cell carcinoma led to signifi-cantly smaller GTVs than those delineated on CT or MRI(10). A comparison with surgical laryngeal specimensshowed that GTVs delineated from 18F-FDG PET were theclosest to the pathologic GTV, whereas the use of CTor MRIled, on average, to an overestimation of the true tumor vol-ume by 40% and 47%, respectively. These results highlightthat the lack of specificity of these anatomic imaging modal-ities may result in inadequate target definition, with possibleconsequences on dose distribution. Although 18F-FDG PETseems a good candidate for radiotherapy planning, its opti-mal use is not a trivial task. The physics of PET, includingpoor statistics and poor spatial resolution, result in highlynoisy and blurred images that may severely affect accuratedetermination of the volume and shape of tumors (Fig. 1).

It is beyond the scope of this article to extensively reviewall available methods for 18F-FDG PET volume segmenta-tion (11). Visual approaches are highly subjective andaffected by display windowing, and methods based on afixed threshold of activity are far too simplistic, as theoptimal threshold varies substantially from case to case.More sophisticated methods include adaptive threshold–based approaches such as signal-to-background ratio, whichwas developed by our group. Although validated, thismethod cannot easily be generalized, as it is dependenton camera and reconstruction algorithm and is not veryaccurate for images with a low signal-to-background ratio,

FIGURE 1. Patient with stage T2 N0 M0 right hypopharyngealHNSCC treated with concomitant chemotherapy andradiotherapy. Patient was imaged with intravenous contrastCT, MRI (fat-saturated [FS] T2-weighted sequence), and 18F-FDG PET before treatment and at end of week 3 (30 Gy).Primary tumor shrinkage was observed with all imagingmodalities but was more dramatic with 18F-FDG PET.

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as observed during treatment. The use of gradient-basedsegmentation represents another method, which was motivatedmainly by the intrinsically low quality of PET images—thatis, the high level of noise and blurred images. Such amethod was made possible by the implementation of spe-cific image restoration tools, that is, edge-preserving filtersfor noise removal and deconvolution algorithms for deblur-ring (12). This segmentation technique has proven to bemore accurate and reliable than threshold-based methods,especially in segmenting images acquired during radiother-apy (13).With these adequate segmentation tools at hand, 18F-

FDG PET appears promising because it provides smaller,more accurate and reproducible GTVs than does CT or MRI(10). More important, refining the GTV delineation bymeans of 18F-FDG PET ultimately led to better dose dis-tributions within planning target volumes and surroundingtissues (9,14). Indeed, the reduction of the primary tumortarget volumes allowed by such an approach translated intosignificant decreases in the volumes receiving the highestdose using either 3-dimensional conformal radiotherapy orintensity-modulated radiotherapy with helical tomotherapy.A prospective multicentric phase II study has been per-formed to clinically validate this concept in HNSCC. Re-sults should be available by mid-2011.In view of the growing role of imaging in target defi-

nition for radiotherapy, one should keep in mind that allmacroscopic modalities available will fail to depict subtletumor extensions and, in particular, the mucosal extent ofthe disease. As shown by Daisne et al. (10), if CT, MRI, and18F-FDG PET overestimate the GTV in most dimensions,all 3 imaging modalities fail to accurately assess themucosal invasion visualized on the macroscopic specimen.In this context, a careful physical examination, includingendoscopy and palpation, still remains the best method forappreciating the mucosal extent of HNSCC.

ADAPTIVE TREATMENT AND THERAGNOSTICS

Significant progress in imaging, dose calculation, anddelivery has recently opened avenues for new treatmentopportunities such as adaptive radiation therapy and dosepainting. Adaptive radiation therapy consists of reassessingtumor volume after a given dose of radiation has beendelivered and then boosting the residual imaged tumor.Preliminary studies have already demonstrated the feasi-bility and usefulness of such approaches in pharyngola-ryngeal squamous cell carcinoma and showed significanttumor shrinkage using both anatomic and functional imag-ing (14). Such approaches, consisting of boosting (dose. 2Gy per fraction) the shrinking tumor volume, are safer thanreducing the irradiated volume, which could lead to missedinvasive cells at the edge (15). The selection of small vol-umes for dose escalation strategies is mandatory to preventunacceptable damage to critical structures embedded withinthe boost volumes, and even more so when a high dose per

fraction is prescribed, such as in simultaneous integratedboost intensity-modulated radiotherapy.

Another appealing approach is the integration of biologicinformation from molecular imaging modalities with thepurpose of targeting radiation-resistant regions inside thetumor, such as high clonogen density, proliferation, orhypoxia, hypothesizing that the regionally variable radio-sensitivity may require a heterogeneous dose distribution toachieve optimal tumor control. In all studies on targetvolume definition conducted so far, it has been assumedthat even when defined with regard to specific biologicpathways, GTVs were homogeneous and did not varyduring the course of radiation treatment. Hence, a radiationdose homogeneously distributed in space and time isdelivered. This assumption is likely an oversimplificationof the biologic reality, as tumors are known to be het-erogeneous with respect to pathways of importance forradiation response, and at least some of them are known toprogressively shrink during treatment.

Bentzen proposed the term theragnostic to describe the useof molecular imaging to prescribe the distribution of radiationdose in 4 dimensions, that is, the 3 spatial dimensions plustime (16). This is undoubtedly a challenging research topicthat could potentially revolutionize the process of radiother-apy planning and delivery. However, before such a dream canbecome a reality, several issues need to be resolved.

One critical issue is the ability to accurately visualize inspace and time the exact location of those clonogenic cellsexpressing a phenotype that may require the delivery of anextra radiation dose. This issue addresses not only theavailability of specific tracers for the various biologic path-ways of interest but also the spatial resolution and correct-ness of the available imaging modalities. In a recent studyperformed on mouse tumor models, Christian et al. foundspatial discrepancies between the PET images and theunderlying microscopic reality represented by autoradiog-raphy images (17). Such differences, attributed to the finiteresolution of PET, were important when small and highlyactive regions of the tumors were considered. Another crit-ical issue for theragnostics is the need to establish corre-spondence between a PET signal intensity (or a PET imagesegmentation) and a prescribed dose, thus evolving the con-cept of dose painting into dose painting by numbers. Asanother challenge, tools are needed to register in space andtime the various images and the dose distribution acquiredthroughout the therapy. To this end, nonrigid registrationtechniques will be required, as tumor or normal-tissueshrinkage is expected during the course of radiotherapytreatment (18). Lastly, from a biologic point of view, thechallenge is to relate a change in tracer uptake to a changein the underlying biology, thus requiring a comprehensivebiologic validation of the concept of dose painting or dosepainting by numbers in experimental models. In summary,although much still needs to be done, it is likely that overthe next 5–10 years we will witness some of our dreamscoming into reality.

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TRACERS OTHER THAN 18F-FDG FOR TARGETVOLUME DELINEATION

The identification of hypoxic tumor volume that can beprescribed higher doses of radiation has been the subject ofnumerous studies. These studies are aimed at identifyingthe best radiopharmaceutical for this particular clinicalsetting. 60Cu- and 64Cu-labeled methylthiosemicarbazone,18F-fluoromisonidazole, and 18F-fluoroazomicyn arabino-side are, among others, the radiopharmaceuticals proposedin these reports (19). Most studies have attempted to iden-tify the hypoxic subvolume within the GTV, to allow theuse of higher doses in the hypoxic cells (20–23). Although18F-fluoromisonidazole has known limitations in contrastresolution and uptake time, studies with this tracer havedemonstrated the possibility of hypoxic volume identifica-tion. Other tracers, such as 18F-fluoroazomicyn arabinosideand methylthiosemicarbazone, are probably going to beapplied in large series of patients. It is hoped that futurelarge clinical trials will demonstrate the usefulness of theseradiopharmaceuticals and improve the selectivity of radia-tion treatments. It is reasonable to forecast that these tracerswill not be used in diagnosis—where 18F-FDG is going toremain the major player—but will find a paramount role inthe biologic characterization of tumors before, during, andafter therapy.Another clinical need for new radiopharmaceuticals de-

rives from the high number of false-positive findings due toinflammatory changes that are reported in 18F-FDG studies.To increase low 18F-FDG specificity, the use of 18F-fluoro-thymidine has been proposed. This tracer probes increasedDNA synthesis and is supposed to be more influenced byinflammatory processes in tissues and lymph nodes. 18F-fluorothymidine PET showed promising results in radiationtherapy applications; therefore, more studies are expectedin the coming years (24). Other compounds—such as 18F-fluoroethyl-tyrosine and 11C-methionine—able to visualizecellular amino acid uptake for protein synthesis have beenproposed as well to increase the specificity of PET (24).Although many other PET compounds are under evalua-tion, 18F-fluorothymidine seems to be the most promisingbecause of its high specificity. In these settings, 18F-FDGwill probably remain the first radiopharmaceutical to beused to study tumors for which it has high sensitivity. Morespecific tracers, such as 18F-fluorothymidine, will be usedas a way to further characterize suspected lesions whenfalse-positive findings cannot be excluded.

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Doi: 10.2967/jnumed.110.075689Published online: February 14, 2011.

2011;52:331-334.J Nucl Med.   Vincent Grégoire and Arturo Chiti  Molecular Imaging in Radiotherapy Planning for Head and Neck Tumors

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