The potential role of non-FDG-PET in the management of head and neck cancer

Oral Oncology 47 (2011) 2–7

Contents lists available at ScienceDirect

Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology

Review

The potential role of non-FDG-PET in the management of head and neck cancer Derrek A. Heuveling a, Remco de Bree a, Guus A.M.S. van Dongen a,b,⇑ a b

Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands Department of Nuclear Medicine and PET Research, VU University Medical Center, Amsterdam, The Netherlands

a r t i c l e

i n f o

Article history: Received 4 August 2010 Received in revised form 15 October 2010 Accepted 17 October 2010 Available online 24 November 2010 Keywords: Positron emission tomography Head and neck cancer Metabolic imaging Hypoxia Molecular imaging Oral cancer

s u m m a r y Positron emission tomography (PET) is a functional imaging modality that is widely used in oncology. The integration of PET with CT (PET–CT) provides at the same time also detailed morphological information, which is especially attractive for the anatomically complex head and neck region. The most widely used PET-tracer for imaging the enhanced metabolism of tumours is 18F-fluorodeoxyglucose (18FDG), but several new tracers for imaging of metabolic features other than glucose consumption (non-FDG tracers) have been developed with the aim to perform better than 18FDG in specific indications. For initial staging of head and neck squamous cell carcinoma (HNSCC) these tracers until now did not show a better performance than 18FDG. Most data suggest a potential role for non-FDG metabolic tracers for treatment response prediction and surveillance of HNSCC. This information may provide a guide for further individualized treatment decisions. The possibility of PET to image biologic features and molecular targets as key drivers of malignant growth and survival provides another important tool for treatment guidance. The presence of the biologic feature hypoxia, a common phenomenon in head and neck cancer, is associated with a poor response to (chemo) radiotherapy. Therefore, knowledge of hypoxia may influence treatment decisions. Several candidate hypoxia PET tracers are discussed. With the increasing knowledge of critical molecular targets in head and neck cancer (e.g. the epidermal growth factor receptor), many novel targeted anticancer therapeutics become available among which monoclonal antibodies and small molecular tyrosin kinase inhibitors. Upon labelling of these drugs with a positron emitter, their distribution within the human body can be quantitatively imaged by PET. In this way, PET can be used for better understanding of in vivo tumour biology, guidance of drug development, and appropriate treatment selection for the individual patient (personalized medicine). Altogether, the potential role of non-FDGPET in the management of HNSCC seems to be guidance and surveillance of treatment of the individual patient. Ó 2010 Elsevier Ltd. All rights reserved.

Introduction Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 5% of all malignant tumours worldwide. Two thirds of the patients with HNSCC present with advanced stage disease. For diagnostic imaging purposes computerized tomography (CT) and magnetic resonance imaging (MRI) are the imaging modalities of first choice, but more advanced imaging modalities have shown to be of complementary value for HNSCC imaging.1 One of these modalities is positron emission tomography (PET). PET requires the administration of a molecule, which is labelled with a positron emitter (i.e. PET tracer). A positron emitter is a radioactive atom that emits a positively charged b-particle (positro⇑ Corresponding author. Department of Otolaryngology/Head and Neck Surgery, nVU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, P.O. ). Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 20 4440953; fax: +31 20 T4443688. he E-mail address: [email protected] (G.A.M.S. van Dongen). 1368-8375/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2010.10.008

distribution of the tracer within the body can be imaged and quantified by a PET or PET–CT camera.2 The most widely used PET tracer in oncology is 18F-fluorodeoxyglucose (18FDG), containing the positron emitter fluorine-18, which has a half-life (t½) of 110 min. 18FDG is a glucose analogue and uptake correlates with glucose uptake of cells. Therefore it can be used to distinguish metabolically active tumour from normal tissues. For HNSCC, 18FDG-PET appeared to be of additional value in particular patient groups. For patients presenting with an unknown primary tumour, 18FDG-PET is able to localize about 25% of these tumours3–5 Furthermore, ‘wholebody’ 18FDG-PET appears to have added value to chest CT for the detection of distant metastases in (advanced stage) HNSCC patients.6–8 18FDG-PET may also be useful in response evaluation and the detection of residual and recurrent disease after nonsurgical treatment. Until now, however, different studies showed inconsistent results. Therefore, further studies are necessary to clarify the exact role of 18FDG-PET and PET–CT for these indications.9–12

D.A. Heuveling et al. / Oral Oncology 47 (2011) 2–7

One of the main drawbacks of 18FDG is the high number of false-positive findings due to (physiologic) uptake of 18FDG in nontumour tissues (e.g. inflammatory tissue).13 Therefore, several other PET-tracers have been developed, with different mechanisms for monitoring the enhanced metabolism of tumour cells, and the aim to perform better than 18FDG for staging purposes and treatment response assessment. In addition to imaging of tumour metabolism, PET also allows for imaging of critical biologic features of tumour tissue (e.g. hypoxia) and for imaging of critical tumour targets and targeted drugs, both approaches aiming to offer the best treatment to the individual patient. This review aims to provide insight in the applications and potentials of non-FDG PET in the management of HNSCC, focusing on imaging of tumour metabolic features other than glucose metabolism, the biologic feature hypoxia, and critical molecular targets involved in tumour growth and survival.

Non-FDG metabolic tracers Imaging of tumour cell proliferation Besides an increased glucose metabolism, which is the mechanism underlying 18FDG uptake, there are several other characteristics of tumour cells which may be exploited for imaging. One of these is the capability of unlimited cell proliferation of a certain tumour cell population. 18F-labelled fluoro-30 -deoxy-30 -L-fluorothymidine (18FLT) is a thymidine analogue. Thymidine is a native nucleoside, which is used by proliferating cells for DNA replication. After uptake in the cell, 18FLT follows the salvage pathway of DNA synthesis and undergoes phosphorylation by thymidine kinase 1 (TK1). TK1 activity is increased in proliferating cells. Unlike thymidine, 18FLT is not incorporated into DNA but trapped in the cytosol. Accumulation in the cytosol forms the basis for 18FLT–PET imaging and reflects cellular proliferation. 18 FLT showed promising results for staging of tumours (Fig. 1) as well as for treatment response evaluation in a majority of tumour types that have been evaluated.14,15 For head and neck cancer, however, there seemed to be no additional value of 18FLT compared to 18FDG regarding staging of tumours.16,17 More promising are the preliminary results suggesting a potential role for 18 FLT-PET in the prediction and monitoring of (early) tumour response to chemoradiation (CRT).15,18–21 Compared to 18FDG, the uptake of 18FLT decreased earlier after initiation of treatment.22,23 Been et al.21 compared both tracers in the same patient group in the evaluation of radiotherapy for laryngeal cancer (n = 10). Sensitivity of 18FLT was lower than for 18FDG in this small patient cohort, but 18FDG produced a false positive scan. Future studies comprising more patients with the aim to compare 18FDG and 18 FLT are warranted to determine the exact (complementary) role of 18FLT for (early) response assessment.

Figure 1 Coronal (A) and transversal (B) fused images of

18

3

Imaging of amino acids metabolism Increased amino acid metabolism is another well-known characteristic of a tumour, in which amino acid transport or protein synthesis rates are enhanced. Therefore, amino acids accumulate in malignant transformed cells. Compared to the glucose derivate 18 FDG, the uptake of amino acids in macrophages and other inflammatory cells is lower, which should theoretically result in a higher specificity. Labelled (natural and unnatural) amino acid analogues like 18FET [O-2-fluoro-(18F)-ethyl-L-thyrosine], 18FMT [L-3-(18F)fluoro-a-methylthyrosine], and 11C-MET [11C-methionine] have been developed as PET ligands for tumour detection. Pauleit et al.24 compared the diagnostic performance of 18FET and 18FDG in 21 patients with suspected head and neck tumours. For staging purposes 18FET showed indeed a higher specificity compared with 18FDG (95% and 79%, respectively), but a lower uptake and sensitivity (75% and 93%, respectively). However, these differences were not statistically significant. Therefore, this tracer may not replace 18FDG for detection of tumours. However, because its better differentiation between inflammatory and malignant tissue, 18FET may be useful for patients with a positive 18FDG scan during follow up after CRT.24,25 18 FMT-PET showed similar results for detection and differentiation of benign and malignant head and neck tumours compared to 18 FDG in a study with 36 patients. However, the contrast of 18FMT uptake between tumours and the surrounding structures was higher than that of 18FDG.26 11 C-MET, a natural amino acid labelled with the positron emitter carbon-11 (11C, t½ = 20 min), has widely been used because of its simple labelling procedure and high uptake by tumours, including (small) head and neck tumours.27–29 However, in comparison with 18FDG, this tracer seems to have similar uptake rates.30,31 For HNSCC, 11C-MET may be of additional value for evaluation of response to treatment. Although Nuutinen et al.32 showed a limited value of 11C-MET after radiotherapy, Chesnay et al.33 showed potential of 11C-MET for early response assessment after chemotherapy in thirteen patients with hypopharyngeal cancer. Therefore, the position of radiolabelled amino acids in the management of HNSCC seems also to be in the treatment response assessment. Again, more studies aiming to assess the performance of radiolabelled amino acids in direct comparison with 18FDG, with larger patient series, are warranted to further address this topic.

Imaging of the biologic feature hypoxia An inadequate supply of oxygen, hypoxia, is an important factor contributing to resistance to radiation and chemotherapy in head and neck cancer. The presence of hypoxia is associated with a more aggressive tumour phenotype, resulting in local tissue invasion and increased metastatic potential. Therefore, hypoxia is an independent

FLT-PET and CT of a patient with a T2 carcinoma of the hypopharynx (arrow).

4

D.A. Heuveling et al. / Oral Oncology 47 (2011) 2–7

negative prognostic factor for tumour progression and outcome of therapy. 34,35 Knowledge about the presence and extent of hypoxic areas provides additional information which may be used to determine the best treatment strategy. Not only if a patient should be treated by radiotherapy, but also how. For example, the concept of ‘‘dosepainting’’ has been introduced in radiotherapy planning. In this concept, a higher dose is administered to the more resistant areas (i.e. hypoxic regions) and a lower dose is administered to the more sensitive parts of a tumour. In this concept, the total administered dose should be equal in all patients.36–38 In addition experimental approaches for the treatment of hypoxic tumours include the addition of the hypoxic cytotoxin tirapazamine or treatment according to the ARCON protocol.39,40 Whether these strategies lead to an improvement of prognosis is subject of ongoing research. There are several methods to determine the presence of hypoxic areas: (1) via direct measurement of tumour oxygen levels obtained from polarographic oxygen electrodes (Eppendorf electrode) inserted into the tumour; (2) via immunohistochemical detection of endogenous proteins which are preferentially expressed under hypoxic conditions 41; and (3) by using nitroimidazole-based drugs which accumulate in hypoxic cells and therefore can be used as reporters of hypoxia. Nitroimidazole-based drugs can either be detected immunohistochemically in tissue samples or upon radiolabelling by PET imaging. Imaging allows for noninvasive in vivo detection and quantification of tissue hypoxia. Another advantage is that both the primary tumour as well as the involved lymph nodes can be visualized, and that detection of heterogeneous intratumoural distribution is possible, although at a millimetre resolution rather than at cell level. The most commonly used PET tracer for hypoxia detection is 18 F-fluoromisonidazole (18FMISO). In hypoxic cells, 18FMISO is trapped, which is the basis for the use of this tracer to measure hypoxia. Thus, high 18FMISO uptake implies a low tissue O2 concentration. 18FMISO was able to detect significant hypoxia in 71–87% of mainly advanced stage HNSCC.42–44 Rajendran et al.43 demonstrated that 18FMISO was able to detect hypoxia before start of treatment in 58 of 73 (79%) (mainly advanced stage) HNSCC patients. All treatments were done with curative intent and consisted of definitive (C)RT or definitive resection with or without adjuvant RT. With a median follow-up time of 72 weeks after 18FMISO-PET, pretherapy 18FMISO uptake appeared to be an independent prognostic factor in head and neck cancer. 18 FMISO is a lipophilic compound and therefore readily crosses cell membranes down concentration gradients. Due to the reduction to a more hydrophilic form in hypoxic cells, it remains trapped intracellularly to a larger extent than in normoxic cells. However, because of the relatively high lipophilicity there is a slow specific accumulation in hypoxic tissue as well as slow clearance from normoxic tissues, resulting in relatively low target-to-background contrast. Ideal hypoxic PET tracers should allow for higher tumour-to-background ratios of radioactivity, which gives better imaging quality. This has led to the development of several other hypoxia specific tracers with more favourable imaging characteristics. 18 FETNIM [18F-labelled fluoroerythronitroimidazole] is a more hydrophilic compound that shows potential for PET imaging.45,46 EF3 [2-(2-nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)-acetamide]47 and EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide]48, both labelled with 18F, are two new PET-tracers for hypoxia detection, which are currently under investigation in clinical studies. A more widely studied compound is 18FAZA [18F-fluoroazomycinarabinofuranoside]. This tracer has shown superior biokinetics compared with 18FMISO in animal tumour models.49–51 A recent study by Postema et al.52, which comprised several tumour types,

revealed that 18FAZA can be considered as a very promising agent for detection of hypoxia, with favorable imaging characteristics. These findings were in agreement with the preliminary results of Souvatzoglou et al.53 They demonstrated in a pilot study (n = 11) that 18FAZA imaging appears feasible in head and neck cancer patients, with adequate imaging quality. Therefore, 18FAZA is a promising agent, but further clinical studies on the direct comparison of 18 FMISO and 18FAZA in HNSCC patients are needed. An important issue for further investigations with these and other novel tracers is the optimal time point for imaging. Anyhow, due to the short half-life of 18F of 110 min, it is not possible to image after hours or even days. Another hypoxia selective PET-tracer that might be clinical useful is the copper(II) complex of diacetyl-2,3-bis(N4-methyl-3-thiosemicarbazonato) ligand [Cu-ATSM] labelled with either 60Cu or 64 Cu. This tracer has been studied in a variety of human solid tumours, including head and neck tumours. While 60Cu has a half-life of 23.7 min, 64Cu has a half-life of 12.7 h, making its use more widely applicable. Both tracers have demonstrated high tumourto-background ratios as early as 30 min after injection for delineating hypoxic tumour tissue and they showed a fast clearance from background. Further studies with this tracer are needed, but results until now are promising.54

PET imaging of molecular targets Recent advances in molecular and cellular biology have facilitated the discovery of novel molecular targets on tumour cells, for example, key molecules involved in proliferation, differentiation, cell death and apoptosis, angiogenesis, invasion and metastases, or associated with cancer cell stemness. This knowledge has boosted the design of cutting-edge targeted pharmaceuticals, with monoclonal antibodies (mAbs) and small molecules e.g. tyrosine kinase inhibitors (TKIs), forming the most rapidly expanding categories. Also in head and neck cancer, several critical molecular tumour targets have been identified, including growth factors and their receptors, which serve as key drivers of tumour growth and progression.55 Well known examples are the epidermal growth factor and its receptor (EGFR), the vascular endothelial growth factor (VEGF) and its receptors, the hepatocyte growth factor and its cMET receptor, and insulin-like growth factor I and its receptor (IGF-IR). Most enthusiasm in targeted therapy of head and neck cancer has been generated with approaches targeting EGFR. In 2006, Bonner et al.56 showed an improvement of locoregional control and reduction of mortality, in patients treated for locoregionally advanced head and neck cancer with concomitant radiotherapy and the anti-EGFR mAb cetuximab compared to radiotherapy alone. On the basis of these results cetuximab became approved by the U.S. Food and Drug Administration (FDA). In the mean time, many more anti-EGFR mAbs (e.g. panitumumab, matuzumab, zalutumumab, and nimotuzumab) and TKIs (e.g. erlotinib, gefitinib, and lapatinib) are under development, along with inhibitors of other critical signal transduction pathways as previously mentioned.57,58 Despite clinical optimism, it is fair to state that the efficacy of current targeted drugs is still limited, with benefit for just a portion of patients. The massive development of new targeted drugs might make optimistic about future perspectives, but also raises the question about how to test all these drugs in an efficient way. Since less than 10% of all anticancer drugs under clinical development will eventually reach the market, it becomes increasingly important to distinguish high from low potential drugs at an early stage. This needs better understanding of the behavior and activity of those drugs in the human body. What is more, the costs of targeted

D.A. Heuveling et al. / Oral Oncology 47 (2011) 2–7

therapies are excessive. Expensive medicines are challenging the health care systems, taking into account that the yearly sales of just mAbs are about 20 billion dollars. The question is how to improve the efficacy of targeted therapies and how to identify patients with the highest chance of benefit. In other words: when, how, and for whom should targeted therapy be reserved. The ability of PET (and PET–CT) to quantitatively image the distribution of radiolabelled drugs within the body makes this technique a valuable tool at several stages of drug development and application. From first-in-man clinical trials with new drugs it is important to learn about the ideal drug dosing for optimal tumour targeting (e.g. saturation of receptors), the uptake in critical normal organs to anticipate toxicity, and the interpatient variations in pharmacokinetics and tumour targeting. Drug imaging might provide this information in an efficient and safe way, with fewer patients treated at suboptimal doses. Pretreatment imaging with the drug of interest might also have added value for patient selection, because it can be used to assess target expression and drug accumulation in all tumour lesions and normal tissues, noninvasively, quantitatively, and even over time. This information might be particularly relevant when targeted drugs are combined with other treatment modalities like chemoand radiotherapy, to find routes of maximum synergism. Ideally, anatomical information on tumour extension is obtained to enable assessment of homogeneity of tumour drug accumulation. Apart from applications in treatment planning, imaging with radiolabelled targeted drugs like mAbs can also be used for diagnostic purposes. To enable visualization of a targeted drug with a PET camera, the drug should be labelled with a positron emitter in an inert way. Moreover, the physical half-life of the positron emitter should be compatible with the residence time of the targeted drug in the body, which is typically several days for slow kinetic intact mAbs and a couple of hours for the fast kinetic small molecules. Due to their large size of 150 kDa, it is quite easy to radiolabel mAbs for PET imaging (called ‘‘immuno-PET’’) in an inert way. Very recently, universal procedures were introduced for radiolabeling of intact mAbs with the long-lived positron emitters iodine-124 (124I, t½ = 100.3 h) and zirconium-89 (89Zr, t½ = 78.4 h), of which 89Zr is particularly suitable in combination with internalizing mAbs.59,60 For radiolabelling of mAb fragments, which are more rapidly cleared from the body than intact mAbs, shorter lived positron emitters became available like gallium-68 (t½ = 1.13 h), copper64 (t½ = 12.7 h), yttrium-86 (t½ = 14.7 h), and bromine-76 (t½ = 16.2 h). In contrast to the labelling of antibodies, radiolabelling of small molecules (<1 kDa) is much more challenging, and needs a drug-specific labelling strategy to assure inertness of labeling. In many cases, labelling with 11C will appear suitable, while in

5

some cases the chemical structure of the drug will also allow labelling with 18F. Imaging of monoclonal antibodies (Immuno-PET) The first clinical immuno-PET study in HNSCC patients was performed with the 89Zr-labelled chimeric mAb U36.61 This mAb is directed against CD44v6, a target associated with tumour metastasis and cancer cell stemness.62 The aim of the trial was to determine the value of immuno-PET with 89Zr-cmAb U36 for detection of lymph node metastases. Twenty HNSCC patients underwent CT and/or MRI and 89Zr-cmAb U36 immuno-PET prior to surgery. Immuno-PET detected all primary tumours (n = 17) as well as lymph node metastases in 18 of 25 positive neck levels.61 Missed lymph nodes were relatively small and contained just a small proportion of tumour tissue. Representative images are shown in Fig. 2. It was concluded that immuno-PET with 89Zr-cmAb U36 performs at least as good as CT/MRI for the detection of HNSCC lymph node metastases (and probably distant metastases). Because of the impressive high resolution images, this study boosted preparations for near future clinical immuno-PET studies, for example with mAbs directed against critical head and neck targets like EGFR63,64, VEGF65, cMet66, carbonic anhydrase IX67, and splice variants of fibronectin and tenascin C which are associated with angiogenesis.68,69 These trials will demonstrate whether immuno-PET imaging will provide a tool for more effective individualized targeted therapy. Imaging of tyrosine kinase inhibitors PET imaging might also contribute to better understanding of TKI activity. For example, erlotinib and gefitinib compete with ATP for the ATP-binding site on the EGFR, thereby preventing signal transduction leading to proliferation. However, the response rate to EGFR TKIs like erlotinib is disappointingly low in HNSCC (4–10%) as well as in non-small cell lung cancer (10–15%), when used as single agents.58,70 Expression and mutation status of the EGFR have been associated with increased response.70 It has been hypothesized that the presence of sensitizing mutations might increase the binding of the drug with its target. This might result in better drug retention within the tumour as well as in a more efficient inhibition of signaling through EGFR. However, for assessment of EGFR expression and mutation status a tumour biopsy has to be taken, which is not always possible. Even when a biopsy is available, it is questionable whether this is sufficient to obtain a representative overview of the whole (often heterogeneous) tumour. Moreover, it is possible that expression and mutation status differ in primary tumour and metastatic lesions and change during the course of disease, for example upon chemo- or radiotherapy.

Figure 2 Fusion (C) of computed tomography (A) and coronal immuno-positron emission tomography (B) images with the zirconium-89-labeled chimeric monoclonal antibody U36 of a head and neck cancer patient with a tumor in the left tonsil and lymph node metastases (small arrows) at the left (level II and III) and right (level II) side of the neck. Images were obtained 72 h postinjection. In these slices, only the lymph node metastases are visible.

6

D.A. Heuveling et al. / Oral Oncology 47 (2011) 2–7

Taking this into account, it might be that PET imaging with the radiolabelled EGFR TKI inhibitor itself gives a more comprehensive overview of EGFR receptor status, and the interaction of the drug with this receptor. To test this possibility, Memon et al.71 evaluated the uptake of 11C-erlotinib in nude mice bearing lung cancer xenograft lines with different sensitivity to erlotinib treatment. In mice carrying the most sensitive xenograft line (with mutation), tumour uptake of 11C-erlotinib was highest, indicating that 11C-erlotinib PET can indeed identify erlotinib sensitive tumours. Aforementioned achievements will pave the way to clinical PET studies with radiolabelled mAbs and TKIs to identify patients which highest chance of benefit from therapy. Conclusions PET imaging may provide additional information in the management of HNSCC patients. The most often used PET tracer is 18 FDG, however, several non-FDG-PET tracers have been developed aiming to perform better than 18FDG. Until now, most data suggest a potential additional value of non-FDG-PET metabolic tracers for treatment response assessment (e.g. 18FLT and radiolabelled amino acids). However, future studies directly comparing the performance of non-FDG-PET tracers with FDG-PET are needed to determine the exact position of non-FDG-PET metabolic tracers. Another non-FDG-PET application is the possibility to image the biologic feature hypoxia. Knowledge of hypoxia may influence treatment decisions: if and how (e.g. ‘‘dose painting’’ or addition of a hypoxia modifier) radiotherapy should be applied. The most commonly used hypoxia PET tracer is 18FMISO, but several other candidates are the subject of ongoing research. In addition, immuno-PET provides information about molecular targets on the tumour and this may be used to select patients most likely to benefit from therapy (e.g. therapy with mAbs or TKI’s). Altogether, the potential role of non-FDG-PET in the management of HNSCC seems to be guidance and surveillance of treatment of the individual patient. Conflicts of interest None declared. Acknowledgments This study was partly performed within the framework of CTMM, The Center for Translational Molecular Medicine (www.ctmm.nl), project AIRFORCE number 03O-103. References 1. De Bree R, Castelijns JA, Hoekstra OS, Leemans CR. Advances in imaging in the work-up of head and neck cancer patients. Oral Oncol 2009;45:930–5. 2. Verel I, Visser GWM, van Dongen GAMS. The promise of immuno-PET in radioimmunotherapy. J Nucl Med 2005;46:164S–71S. 3. Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer 2004;101:2641–9. 4. Johansen J, Buus S, Loft A, Keiding S, Overgaard M, Hansen HS, et al. Prospective study of FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor Results from the Dahanca-13 study. Head Neck 2008;30:471–8. 5. Roh JL, Kim JS, Lee JH, Cho KJ, Choi SH, Nam SY, et al. Utility of combined 18Ffluorodeoxyglucose-positron emission tomography and computed tomography in patients with cervical metastases from unknown primary tumors. Oral Oncol 2009;45:218–24. 6. Ng SH, Chan SC, Liao CT, Chang JT-C, Ko SF, Wang HM, et al. Distant metastases and synchronous second primary tumors in patients with newly diagnosed oropharyngeal and hypopharyngeal carcinomas: Evaluation of 18F-FDG PET and extended-field multi-detector row CT. Neuroradiology 2008;50:969–79. 7. Senft A, de Bree R, Hoekstra OS, Kuik DJ, Golding RP, Oyen WJG, et al. Screening for distant metastases in head and neck cancer patients by chest CT or whole body FDG-PET: A prospective multicenter trial. Radiother Oncol 2008;87:221–9.

8. Krabbe CA, Pruim J, van der Laan BFAM, Rodiger LA, Roodenburg JLN. FDG-PET and detection of distant metastases and simultaneous tumors in head and neck squamous cell carcinoma: A comparison with chest radiography and chest CT. Oral Oncol 2009;45:234–40. 9. De Bree R, Van der Putten L, Brouwer J, Castelijns JA, Hoekstra OS, Leemans CR. Detection of locoregional recurrent head and neck cancer after (chemo)radiotherapy using modern imaging. Oral Oncol 2009;45:386–93. 10. Isles MG, McConkey C, Mehanna HM. A systematic review and meta-analysis of the role of positron emission tomography in the follow up of head and neck squamous cell carcinoma following radiotherapy or chemoradiotherapy. Clin Otolaryngol 2008;33:210–22. 11. Yao M, Smith RB, Hoffman HT, Funk GF, Lu M, Menda Y, et al. Clinical significance of postradiotherapy [18F]-fluorodeoxyglucose positron emission tomography imaging in management of head-and-neck cancer-a long-term outcome report. Int J Radiat Oncol Biol Phys 2009;74:9–14. 12. Moeller BJ, Rana V, Cannon BA, Williams MD, Sturgis EM, Ginsberg LE, et al. Prospective risk-adjusted [18F] fluorodeoxyglucose positron emission tomography and computed tomography assessment of radiation response in head and neck cancer. J Clin Oncol 2009;27:2509–25. 13. Burrell SC, Van den Abbeele AD. 2-Deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography of the head and neck: an atlas of normal uptake and variants. Mol Imaging Biol 2005;7:244–56. 14. Larson SM, Schoder H. New PET tracers for evaluation of solid tumor response to therapy. Q J Nucl Med Mol Imaging 2009;53:158–66. 15. Barwick T, Bencherif B, Mountz JM, Avril N. Molecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: a comprehensive evaluation. Nucl Med Comm 2009;30:908–17. 16. Cobben DCP, van der Laan BFAM, Maas B, Vaalburg W, Suurmeijer AJH, Hoekstra HJ, et al. 18F-FLT PET for visualization of laryngeal cancer: comparison with 18F-FDG PET. J Nucl Med 2004;45:226–31. 17. Troost EGC, Vogel WV, Merkx MAW, Slootweg PJ, Marres HAM, Peeters WJM, et al. 18F-FLT PET does not discriminate between reactive and metastatic lymph nodes in primary head and neck cancer patients. J Nucl Med 2007;48:726–35. 18. Troost EGC, Bussink J, Hoffmann AL, Boerman OC, Oyen WJG, Kaanders JHAM. 18 F-FLT PET/CT for early response monitoring and dose escalation in oropharyngeal tumors. J Nucl Med 2010;51:866–74. 19. Menda Y, Boles Ponto LL, Dornfeld KJ, Tewson TJ, Watkins GL, Schultz MK, et al. Kinetic analysis of 3’-deoxy-3’-18F-fluorothymidine (18F-FLT) in head and neck cancer patients before and early after initiation of chemoradiation therapy. J Nucl Med 2009;50:1028–35. 20. De Langen AJ, Klabbers B, Lubberink M, Boellaard R, Spreeuwenberg MD, Slotman BJ, et al. Reproducibility of quantitative 18F-3’-deoxy-3fluorothymidine measurements using positron emission tomography. Eur J Nucl Med Mol Imaging 2009;36:389–95. 21. Been LB, Hoekstra HJ, Suurmeijer AJH, Lager PL, Van der Laan BFAM, Elsinga PH. [18F]FLT-PET and [18F]FDG-PET in the evaluation of radiotherapy for laryngeal cancer. Oral Oncol 2009;45:e211–5. 22. Sugiyama M, Sakahara H, Sato K, Harada N, Fukumoto D, Kakiuchi T, et al. Evaluation of 3’-deoxy-3’-18F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice. J Nucl Med 2004;45:1754–8. 23. Molthoff CFM, Klabbers BM, Berkhof J, Felten JT, Van Gelder M, Windhorst AD, et al. Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice. Comparison of 2’-deoxy-2’-[18F]fluoro-D-glucose (FDG) and 3’-[18F]fluoro-3’-deoxythymidine (FLT). Mol Imaging Biol 2007;9:340–7. 24. Pauleit D, Zimmermann A, Stoffels G, Bauer D, Risse J, Fluss MO, et al. 18F-FET PET compared with 18F-FDG PET and CT in patients with head and neck cancer. J Nucl Med 2006;47:256–61. 25. Balogova S, Perie S, Kerrou K, Grahek D, Montravers F, Angelard B, et al. Prospective comparison of FDG and FET PET/CT in patients with head and neck squamous cell carcinoma. Mol Imaging Biol 2008;10:364–73. 26. Miyakubo M, Oriuchi N, Tsushima Y, Higuchi T, Koyama K, Arai K, et al. Diagnosis of maxillofacial tumor with L-3-[18F]-fluoro-alpha-methyltyrosine (FMT) PET: a comparative study with FDG-PET. Ann Nucl Med 2007;21: 129–35. 27. Leskinen-Kallio S, Nagren K, Lehikoinen P, Ruotsalainen U, Teras M, Joensuu H. Carbon-11-Methionine and PET is an effective method to image head and neck cancer. J Nucl Med 1992;33:691–5. 28. Lindholm P, Leskinen S, Lapela M. Carbon-11-Methionine uptake in squamous cell head and neck cancer. J Nucl Med 1998;39:1393–7. 29. Wedman J, Pruim J, Langendijk JA, Van der Laan BFAM. Visualisation of small glottic laryngeal cancer using methyl-labeled 11C-methionine positron emission tomography. Oral Oncol 2009;45:703–5. 30. Lindholm P, Leskinen-Kallio S, Minn H, Bergman J, Haaparanta M, Lehikoinen P, et al. Comparison of fluorine-18F-fluorodeoxyglucose and carbon-11methionine in head and neck cancer. J Nucl Med 1993;34:1711–6. 31. Geets X, Daisne JF, Gregoire V, Hamoir M, Lonneux M. Role of 11C-methionine positron emission tomography for the delineation of the tumor volume in pharyngo-laryngeal squamous cell carcinoma: Comparison with FDG-PET and CT. Radiother Oncol 2004;71:267–73. 32. Nuutinen J, Jyrkkio S, Lehikoinen P, Lindholm P, Minn H. Evaluation of early response to radiotherapy in head and neck cancer measured with [11C]methionine-positron emission tomography. Radiother Oncol 1999;52: 225–32. 33. Chesnay E, Babin E, Constans JM, Agostini D, Bequignon A, Regeasse A, et al. Early response to chemotherapy in hypopharyngeal cancer: assessment with

D.A. Heuveling et al. / Oral Oncology 47 (2011) 2–7

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

11 C-methionine PET, correlation with morphologic response, and clinical outcome. J Nucl Med 2003;44:526–32. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997;38:285–9. Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 2005;77:18–24. Ling CC, Humm J, Larson S, Amols H, Fuks Z, Leibel S, et al. Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality. Int J Radiat Oncol Biol Phys 2000;47:551–60. Grosu AL, Souvatzoglou M, Roper B, Dobritz M, Wiedenmann N, Jacob V, et al. Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. Int J Radiat Oncol Biol Phys 2007;69:541–51. Lambin P, Petit SF, Aerts HJWL, Van Elmpt WJC, Oberije CJG, Starmans MHW, et al. The ESTRO Breur Lecture 2009. From population to voxel-based radiotherapy: exploiting intra-tumour and intra-organ heterogeneity for advanced treatment of non-small cell lung cancer. Radiother Oncol 2010;96(2):145–52. Kaanders JHAM, Pop LAM, Marres HAM, Bruaset I, Van den Hoogen FJA, Merkx MAW, et al. ARCON: experience in 215 patients with advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002;52:769–78. Rischin D, Peters LJ, O’Sullivan B, Giralt J, Fisher R, Yuen K, et al. Tirapazamine, cisplatin, and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol 2010;28:2989–95. Russell J, Carlin S, Burke SA, Wen B, Yang KM, Ling CC. Immunohistochemical detection of changes in tumor hypoxia. Int J Radiat Oncol Biol Phys 2009;73:1177–86. Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, et al. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of TransTasman Radiation Oncology Group Study 98.02. J Clin Oncol 2006;24:2098–104. Rajendran JG, Schwartz DL, O’Sullivan J, Peterson LM, Ng P, Scharnhorst J, et al. Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin Cancer Res 2006;12:5435–41. Hicks RJ, Rischin D, Fisher R, Binns D, Scott AM, Peters LJ. Utility of FMISO PET in advanced head and neck cancer treated with chemoradiation incorporating a hypoxia-targeting chemotherapy agent. Eur J Nucl Med Mol Imaging 2005;32:1384–91. Gronroos T, Bentzen L, Marjamaki P, Murata R, Horsman MR, Keiding S, et al. Comparison of the biodistribution of two hypoxia markers [18F]FETNIM and [18F]FMISO in an experimental mammary carcinoma. Eur J Nucl Med Mol Imaging 2004;31:513–20. Gronroos T, Eskola O, Lehtio K, Minn H, Marjamaki P, Bergman J, et al. Pharmacokinetics of [18F]FETNIM: a potential marker for PET. J Nucl Med 2001;42:1397–404. Mahy P, Geets X, Lonneux M, Leveque P, Christian N, De Bast M, et al. Determination of tumour hypoxia with [18F]EF3 in patients with head and neck tumours: a phase I study to assess the tracer pharmacokinetics, biodistribution and metabolism. Eur J Nucl Med Mol Imaging 2008;35:1282–9. Komar G, Seppanen M, Eskola O, Lindholm P, Gronroos TJ, Forsback S, et al. 18FEF5: A new PET tracer for imaging hypoxia in head and neck cancer. J Nucl Med 2008;49:1944–51. Piert M, Machulla HJ, Picchio M, Reischl G, Ziegler S, Kumar P, et al. Hypoxiaspecific tumor imaging with 18F-fluoroazomycin arabinoside. J Nucl Med 2005;46:106–13. Reischl G, Dorow DS, Cullinane C, Katsifis A, Roselt P, Binns D, et al. Imaging of tumor hypoxia with [124I]IAZA in comparison with [18F]FMISO and [18F]FAZA– first small animal PET results. J Pharm Pharm Sci 2007;10:203–11. Sorger D, Patt M, Kumar P, Wiebe LI, Barthel H, Seese A, et al. [18F]Fluoroazomycinarabinofuranoside (18FAZA) and [18F]Fluoromisonidazole

52.

53.

54.

55. 56.

57. 58. 59.

60.

61.

62.

63.

64.

65.

66.

67.

68. 69.

70.

71.

7

(18FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors. Nucl Med Biol 2003;30:317–26. Postema EJ, McEwan AJB, Riauka TA, Kumar P, Richmond DA, Abrams DN, et al. Initial results of hypoxia imaging using 1-alpha-D-(5-deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole 18F-FAZA). Eur J Nucl Med Mol Imaging 2009;36:1565–73. Souvatzoglou M, Grosu AL, Roper B, Krause BJ, Beck R, Reischl G, et al. Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study. Eur J Nucl Med Mol Imaging 2007;34:1566–75. Holland JP, Lewis JS, Dehdashti F. Assessing tumor hypoxia by positron emission tomography with Cu-ATSM. Q J Nucl Med Mol Imaging 2009;53:193–200. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008;359:1143–54. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–78. Seiwert TY, Cohen EEW. Targeting angiogenesis in head and neck cancer. Semin Oncol 2008;35:274–85. Bernier J, Bentzen SM, Vermorken JB. Molecular therapy in head and neck oncology. Nat Rev Clin Oncol 2009;6:266–77. Van Dongen GAMS, Visser GWM, Lub-De Hooge MN, De Vries EG, Perk LR. Immuno-PET: A navigator in monoclonal antibody development and applications. Oncologist 2007;12:1379–89. Van Dongen GAMS, Vosjan MWJD. Immuno-positron emission tomography: shedding light on clinical antibody therapy. Cancer Biother Radiopharm 2010;25(4):375–85. Borjesson PKE, Jauw YWS, Boellaard R, de Bree R, Comans EFI, Roos JC, et al. Performance of immuno-positron emission tomography with zirconium-89labeled chimeric monoclonal antibody U36 in the detection of lymph node metastases in head and neck cancer patients. Clin Cancer Res 2006;12:2133–40. Schrijvers AHGJ, Quak JJ, Uyterlinde AM, van Walsum M, Meijer CJLM, Snow GB, et al. MAb U36, a novel monoclonal antibody successful in immunotargeting of squamous cell carcinoma of the head and neck. Cancer Res 1993;53:4383–90. Aerts HJWL, Dubois L, Perk L, Vermaelen P, van Dongen GAMS, Wouters BG, et al. Disparity between in vivo EGFR expression and 89Zr-labeled cetuximab uptake assessed with PET. J Nucl Med 2009;50:123–31. Perk LR, Visser GWM, Vosjan MJWD, Stigter-van Walsum M, Tijink BM, Leemans CR. Et al. 89Zr as a PET surrogate radioisotope for scouting biodistribution of the therapeutic radiometals 90Y and 177Lu in tumor-bearing nude mice after coupling to the internalizing antibody cetuximab. J Nucl Med 2005;46:1898–906. Nagengast WB, de Vries EG, Hospers GA, Mulder NH, de Jong JR, Hollema H, et al. In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. J Nucl Med 2007;48:1313–9. Perk LR, Stigter-van Walsum M, Visser GWM, Kloet RW, Vosjan MJWD, Leemans CR, et al. Quantitative PET imaging of Met-expressing human cancer xenografts with 89Zr-labelled monoclonal antibody DN30. Eur J Nucl Med Mol Imaging 2008;35:1857–67. Brouwers A, Verel I, Van Eerd J, Visser G, Steffens M, Oosterwijk E, et al. PET radioimmunoscintigraphy of renal cell cancer using 89Zr-labeled cG250 monoclonal antibody in nude rats. Cancer Biother Radiopharm 2004;19:155–63. Neri D, Bicknell R. Tumour vascular targeting. Nat Rev Cancer 2005;5:436–46. Tijink BM, Perk LR, Budde M, Stigter-van Walsum M, Visser GWM, Kloet RW, et al. 124I–L19-SIP for immuno-PET imaging of tumour vasculature and guidance of 131I–L19-SIP radioimmunotherapy. Eur J Nucl Med Mol Imaging 2009;36:1235–44. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32. Memon AA, Jakobsen S, Dagnaes-Hansen F, Sorensen BS, Keiding S, Nexo E. Positron emission tomography (PET) imaging with [11C]-labeled erlotinib: a micro-PET study on mice with lung tumor xenografts. Cancer Res 2009;69:873–8.