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The Evolving Role of Positron Emission Tomography-Computed Tomography in Organ-Preserving Treatment of Head and Neck Cancer
The Evolving Role of Positron Emission Tomography-Computed Tomography in Organ-Preserving Treatment of Head and Neck Cancer Madhur K. Garg, MD, Jonathan Glanzman, MD, and Shalom Kalnicki, MD The introduction of image-guided radiation therapy and intensity-modulated radiation therapy has led to unparalleled advances in achieving precise dose conformality in radiation therapy and ushered in new possibilities in organ preservation. Without the ability to meticulously delineate radiation treatment volumes, these advantages would be clinically irrelevant. Positron emission tomography (PET)/computed tomography (CT) has revolutionized the management of head and neck cancers in all areas, including diagnosis, staging, radiation treatment planning, and response evaluation. It has been shown to have a superior sensitivity for defining primary disease and both higher sensitivity and specificity for nodal disease in comparison with CT or magnetic resonance imaging during treatment planning. Thus, PET/CT frequently leads to an alteration of gross tumor volume/clinical target volume/planning target volume and often changes a patient’s tumor, nodes, metastases staging. According to our data, the addition of PET to CT alone led to a modification in treatment planning in 55% of patients studied. PET/CT also helps to standardize radiation therapy between institutions and decreases interobserver variability. PET/CT is a powerful predictor of outcome after treatment. Although technical obstacles do exist and PET/CT does have small inherent inaccuracies, these can usually be overcome with careful planning and specification of setup error/margins, thereby allowing PET/CT to remain an essential and necessary tool in our fight against head and neck cancers. Semin Nucl Med 42:320-327 © 2012 Elsevier Inc. All rights reserved.
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ositron emission tomography (PET)/computed tomography (CT) has emerged as an essential tool in the management of squamous cell carcinomas of the head and neck; it plays a key role in diagnosis, staging, and response evaluation, and it has gained tremendous relevance in radiation treatment. In fact, the biological complexity of head and neck cancers, the multiple structures it can invade, and the sparing of essential normal tissues to decrease morbidity make PET/CT a major addition to our therapeutic armamentarium. The recent development of intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy has resulted in such radiation dose conformality that the radiation oncologist can address the target tumor with higher radiobiological effectiveness while leading to increased normal tissue sparing (Fig. 1). This translates into im-
Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY. Address reprint requests to Shalom Kalnicki, MD, Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467-2401. E-mail: skalnick@ montefiore.org.
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proved local control rates with decreased treatment-related morbidity. Especially in cancers of the head and neck, where the confluence of small normal structures within a complex anatomical region makes conventional radiation extremely toxic, IMRT driven “dose sculpting” has decreased the morbidities of radiation therapy, notably xerostomia, osteoradionecrosis, and swallowing dysfunction, with significant improvement of quality of life.1-4 In addition, the simultaneous administration of chemotherapy and radiation, although leading to improved local control and survival in locally advanced head and neck cancers, amplifies morbidities to such an extent that before the IMRT era many patients did not complete therapy; these new techniques have changed this scenario dramatically.5 Improved results with radiation treatment, especially associated with chemotherapy, have thus heralded the era of organ preservation in head and neck cancer. Organ preservation requires relatively high doses of radiation (66-72 Gy in 33-39 daily fractions or 74-82 Gy in 62-68 fractions twice per day) to the gross tumor in the primary site and areas of gross nodal metastases. In the postoperative setting for high-risk
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Figure 1 An example of a head and neck intensity-modulated radiation therapy (IMRT) plan and field arrangement with multiple beams, allowing for improved dose conformality.
patients (ie, extracapsular nodal extension, close margins), the tumor bed and nodal areas will often be treated to a dose of 66-72 Gy delivered in 33-39 treatment sessions. Normal tissue tolerance to radiation treatment is dependent on the tissue being treated, the volume of tissue irradiated, and sensitizing agents, such as chemotherapy.6 In head and neck IMRT irradiation, the parotid glands are commonly constrained to a mean dose of 26 Gy, spinal cord dose is almost invariably kept below 45 Gy, the mandible below 70 Gy, and the superior pharyngeal constrictor muscles have a maximum tolerable dose of 45 Gy. It becomes immediately obvious how the normal tissue tolerance doses are significantly lower than the tumor target doses outlined previously and by the proximity of these normal tissues to the tumor harboring structures (Fig. 2). It is thus essential to define radiation volumes that are both necessary and sufficient for proper dose delivery. Inadequate coverage to tumor and nodal targets with their proper dose (geographic miss) would dramatically increase the propensity for locoregional and subsequent distant failure. Excessive expansion of target volumes will produce dose deposition in normal tissues and severely increase treatment morbidity. Establishing and contouring the exact target volumes is the major determinant of outcome; the gross tumor volume (GTV) is established with imaging and clinical examination; the clinical target volume consists of nodal areas or anatomical compartments that are known to be at risk for microscopic involvement; finally, the planning target volume (PTV) includes a three-dimensional expansion to account for daily treatment setup inaccuracies. To these traditional definitions, some authors now add the concept of biological target volume as determined by PET/CT.7
PET/CT in Radiation Planning The sensitivity of anatomically based imaging for head and neck cancer at the primary site is less than ideal, with 50%95% for CT and 68%-92% for magnetic resonance imaging (MRI). Bulky nodal involvement in the neck is easily detected clinically, but for smaller and intermediate-sized nodes, the sensitivity of CT for metastases is 65%-95%, whereas for MRI is 35%-90%. For both modalities, specificity is a function of size. PET/CT with 18F-fluorodeoxyglucose (FDG) is useful for determining tumor location, stage, persistence, and recurrence in head and neck cancer. Its usage has been increasing secondary to its high sensitivity (90%-96%) at the primary site and high sensitivity (85%-90%) and specificity (70%95%) in nodal areas8,9 (Fig. 3). It is especially valuable in detection of primary site in tumors that manifest itself as nodal metastasis without a clinically evident primary site.10 In preradiation scanning, PET/CT is accepted as significantly superior to PET alone in identification of areas of tumor involvement11,12 with a sensitivity of 96% and specificity of 98.5%.13 There is abundant evidence supporting the routine use of PET/CT in targeting head and neck cancers with radiation. Daisne et al14 compared CT-, MRI-, and PET-delineated volumes in 29 patients with oropharyngeal, hypopharyngeal, or laryngeal tumors, including analysis of surgical specimens in 9 patients who underwent a total laryngectomy; nodal volumes were not outlined. Surgical specimen was significantly smaller compared with all 3 imaging modalities (CT ⫽ 20.8 cm3, MRI ⫽ 23.8 cm3, PET ⫽ 16.3 cm3, surgical specimen ⫽ 12.6 cm3). PET volumes were significantly smaller than the other 2 imaging modalities. Most strikingly, no imaging mo-
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Figure 2 In this head and neck IMRT plan, one can see the dose sculpting and organ preservation that IMRT creates. (A and B) Organ preservation of larynx and left parotid. (C) An example of dose volume histograms.
dality fully represented superficial extent of tumor, with underestimation of superficial tumor extension in the mucosa of the contralateral larynx and extralaryngeal extension. Nishioka et al15 performed FDG-PET and MRI or CT in treatment planning position in 21 patients, 19 of which did not have a significant change in delineated volumes between treatment modalities; 4 patients had an increase in nodal staging, completely changing their target volumes and therapeutic approach. The feasibility of coregistering PET/CT data into computerized radiation therapy planning systems became evident more than a decade ago. Ciernik et al16 successfully coregistered PET/CT with noncontrast treatment planning CT in 12 patients, noting 50% change in GTV of 25% of greater on PET/CT compared with CT alone. Four patients had a decrease in GTV of 10% or more on PET/CT, and 16% of these patients were found to have distant metastases on initial staging PET/CT, eliminating ineffective local treatment in 25% of patients studied. Heron et al17 conducted one of the first systematic comparative reviews between volumes delineated with contrast CT alone versus PET/CT-derived targets. The authors found volumes of primary disease delineated on CT
to be up to 3-fold larger than volumes delineated on PET/CT. This statistically significant finding may be skewed by 1 patient with carcinoma of the base of tongue in which the CT volume was 23 times larger than the PET/CT volume. In addition, in 1 patient with carcinoma of the oral tongue, the CT volume was 9.5-fold larger than the PET/CT volume. It is unclear what role any streak artifacts from dental implants may have played in the wide variability between CT and PET/CT volumes in these 2 patients. There was no statistically significant difference in nodal volumes outlined between CT and PET/CT. PET/CT also influenced treatment management, as additional 3 patients were found to have nodal metastatic disease. Similar results were reported by Paulino et al18 who found that tumor size decreased when delineated by PET/CT in 30/40 patients, whereas 7/40 had an increase in size; median GTV on PET is smaller than on CT (37 vs 20.3 cm3). Similar results were obtained by several other authors.19-21 In our institution, Ahn and colleagues22 analyzed 46 patients for CT alone versus PET/CT volume differences in both the primary site and the neck; 21% of patients had an increase in the number of nodes detected on PET/CT compared
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volume dose for microscopic disease into GTV dose for gross disease. The importance of this added dose could not be overemphasized, as it may lead to improved outcomes. Accounting for differences in volumes and doses, the authors estimated that the addition of PET/CT to CT alone changed radiation planning in approximately 55% of patients.
Issues and Controversies Interobserver variability in outlining the radiation target volumes is a matter of high importance in modern radiation oncology, affecting clinical trials and outcomes reporting. The use of PET/CT can decrease this variability by adding an additional parameter with standardized volumes. In the study of Ciernik et al,16 the use of PET/CT significantly de-
Figure 3 In this postoperative squamous cell carcinoma of the anterior tongue, persistent/recurrent disease was noted on positron emission tomography (PET) but not visualized on postoperative computed tomography (CT).
with CT (Fig. 4), whereas 14% had a decrease in the number of nodes detected on CT; 23% of patients had a larger volume (110%) drawn on PET/CT than on CT, whereas 54% of patients had a smaller volume (90%) delineated on PET/CT than on CT (Fig. 5). In general, PET/CT volumes of the primary lesions tend to be smaller than CT ones, as one clearly separates inflammatory mucosal and submucosal components of the mass lesion; in a smaller number of cases, especially base of tongue, PET/CT adds volume by identifying disease lying within or adjacent to muscle layers and infiltrative neoplastic processes, which appear normal on CT (Fig. 6). For nodal disease, there is little volume variability but PET/CT adds value by identifying abnormal uptake in nodes that appear normal on CT by volume only (⬍1 cm). In this case, there is a change in the patient’s tumor, nodes, metastases staging, leading to a transformation of clinical target
Figure 4 In this patient with base of tongue carcinoma, a right fluorodeoxyglucose avid node is detected on PET/CT, not easily visualized on CT alone.
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M.K. Garg, J. Glanzman, and S. Kalnicki (SUV) value as determined by PET phantom, 50% isointensity level, and others. A popular technique has been fixed threshold of the background-subtracted tumor maximum uptake, usually 40%-50%. Ashamalla et al23 have suggested inclusion of the “halo” of the PET-avid mass. FDG-PET in its current form is not an extremely accurate test, with a spatial resolution of approximately 0.4-0.7 cm. This is dependent both on the intrinsic physical properties of the scanner, as well as the distance traveled by the positron from the 18F-moiety of FDG before photon– electron pair annihilation. The magnitude of the spatial resolution uncertainty is considered to be a function of tumor size. In radiation oncology planning, the portion of the GTV expansion to generate PTV includes margin to account for microscopic extension of the tumor, which may not be evident on imaging. At our institution, common practice in the head and neck is to have a 0.5-cm expansion on GTV in the PTV to account for this microscopic extension, with a further 0.5-cm expansion to account for setup error or patient movement. In this case, considering that the most likely spatial resolution error would be 0.5 cm, for a worst-case scenario, the delineated tumor in one dimension could be overestimated by 1 cm. At the other extreme, there would be enough margins to account for setup error with a 0.5 cm GTV to PTV expansion.
Non-FDG-PET Probes
Figure 5 In this patient with base of tongue carcinoma, an example of the PET avid volume being smaller than the gross tumor volume (GTV) delineated on CT alone.
creased the mean volume difference between 2 contouring radiation oncologists by a multiple of 4 or 17 cm3. This observation appears to conflict with the findings of Riegel et al19 and is likely because of a standardized threshold algorithm used by Ciernik. When delineating tumor on PET, selection of the threshold algorithm can lead to large differences in outlined volume. The issue of threshold determination is controversial, and investigators have used several different techniques. This varies between arbitrary threshold levels, liver uptake normalization, 50% of maximal standardized uptake value
Hypoxia PET markers are of potential great interest in radiation treatment planning.24 Chronically hypoxic cells are relatively radioresistant because they lack sufficient oxygen for fixation of free radical damage and consequent apoptosis. These areas can be detected using markers conjugated to misonidazole, tirapazamine, and other agents that act via the inherent affinity of these molecules for electron-rich reductive states. These hypoxic areas are candidates to receive radiation doses of 70 Gy or more. Because of this property, these agents also act as hypoxic cell sensitizers by causing fixation of radiation-induced damage in a manner similar to that of oxygen. Trials of hypoxia markers as radiation sensitizers have been largely negative, with the notable exception of nimorazole in a subset of patients with pharyngeal and supraglottic larynx tumors.25 Additional imaging strategies with reporter gene imaging may potentially have utility in identifying areas of tumor spread26 and in their radiotherapy targeting with an 18F-fluoroazomycinarabinoside marker.27 Tumor flow and oxygenation are essential for radiation response. Lehtio et al28 measured oxygenation status using 18F-fluoroerythronitroimidazole in addition to standard FDG PET to determine the fractional hypoxic volume and tumor blood flow. In a study of 21 patients, the ones with fractional hypoxic volume greater than the median had significantly worse local control and survival, pointing toward the importance of establishing the presence and location of hypoxia.28 In our institution, we are studying the potential implications of an 2-(5-fluoro-pentyl)-2-methyl-malonic acid, [18F]ML-10 apoptosis marker in early response evaluation of patients undergoing head and neck cancer chemo-irradiation.
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Figure 6 The use of PET in a 45-year-old male patient with a locally advanced supraglottic tumor treated to a dose of 70 Gy. The PET/CT was fused with the treatment planning CT. PET allows for the sparing of essential normal tissue and organ preservation in head and neck cancer while allowing for the identification and contouring of exact tumor volumes with a sensitivity of 90%-96% at the primary site. A smaller more precise GTV for the primary lesion is defined with the use of PET, whereas a CT alone cannot differentiate between inflammatory mucosal and submucosal components and would lead to GTV overestimation. Arrow signifies GTV after PET fusion.
Response Evaluation and Risk Adaptive Therapy The use of PET as a noninvasive surrogate for assessing response to therapy with organ-sparing chemoradiation is currently being assessed. Restaging through PET for restaging yields a sensitivity of approximately 80%-95%, a specificity of 75%-90%, and an accuracy of 80%-90%. In a study of 28 head and neck patients, PET/CT performed 8 weeks after definitive radiotherapy had a sensitivity of 77% and specificity of 93%, in comparison with a sensitivity and specificity of 86% and 58% for contrast-enhanced CT.29-30 A series of 12 patients with a clinically palpable residual neck mass found that PET/CT was highly accurate in the determination of residual tumor.31 Time-honored assessment methods rely heavily on physical examination, as imaging techniques have been lacking. At the University of Winsconsin, Zundel et al32 compared posttreatment PET/CT with physical examination for detection of locoregional failures, finding a sensitivity of 100% versus 50% and specificities of 64.6% versus 89.6%, establishing that a negative PET/CT after therapy is much more indicative of local control than a negative physical examination. Brun et al studied 47 patients with stage II-IV squamous cell carcinomas with 2 PET/CT examinations, one before and one 1-3 weeks after definitive treatment; metabolic rate (MR) and SUV were measured. After a median follow-up time of 3.3 years, the authors found that lower metabolic rate and SUV were significantly associated with complete response.33 At the University of Iowa, Yao et al31 reported on 12 patients who underwent neck dissections for residual lymphadenopathy after irradiation. All patients with a negative or maximum nodal SUV ⬍3 postradiation PET had a negative neck dissection; hence, a neck dissection can be avoided on basis of the postradiation PET scan. Deploying that strategy
on a larger sample of 53 patients, with 70 heminecks available for analysis, the authors concluded that neck dissection can be safely omitted in patients with small residual adenopathy on CT but with a negative PET 12 weeks after irradiation.34 The same group studied 64 patients who had a negative first PET/CT after treatment; 40 remained locoregionally controlled, whereas 3 developed distant metastasis; only 1 of 45 patients with an initially negative study developed local recurrence; none of 49 patients with a negative neck on PET/CT developed a neck recurrence, making a negative PET an excellent marker for nodal disease control. Six of 11 patients with positive posttreatment studies at the primary site had persistent disease, allowing for salvage surgery to be deployed in a timely fashion.35 The University of Pittsburgh group used its early experience in PET radiation planning to analyze timing and sensitivity of response evaluation after therapy. Andrade et al found a sensitivity of 76.9% and specificity of 93.3% for PET/CT scans 8 weeks after completing therapy in the first series of 28 patients.30 Passero et al analyzed 53 patients with previously untreated stages III-IVb disease, treated with primary concurrent chemoradiotherapy. Response was assessed by clinical examination, CT, and PET portions of combined PET/CT scan approximately 8 weeks after completion of treatment. Complete response (CR) rates were clinical examination ⫽ 42/53 (79%), CT ⫽ 15/53 (28%), and PET/CT ⫽ 27/53 (51%). On statistical analysis, CR as assessed by PET, but not as assessed by clinical examination or CT using response criteria evaluation for solid tumors criteria, correlated significantly with progression-free status (P ⬍ 0.0001). The 2-year progression-free survival for patients with CR and without CR by PET was 93% and 48%, respectively (P ⫽ 0.0002). A negative PET scan on combined PET/CT after chemoradiotherapy is a powerful predictor of outcome, and
326 PET/CT significantly improved the accuracy of posttreatment assessment by CT.36 As always, standardizing what uptake could be identified with recurrent or persistent disease is a controversial point. The Stanford group performed a detailed analysis of 47 patients who underwent posttreatment PET, applying Cox regression models to different levels of uptake. They found a highly significant statistical correlation with the metabolic tumor volume above 2.0. An increase in metabolic tumor volume above 2.0 represented hazard ratios of approximately 2.1 for disease-free survival and 2.0 for overall survival after chemoirradiation for head and neck cancer.37 The group further validated their findings for human papillomavirus-positive and -negative head and neck cancers, in a study of 83 patients.38 Other sophisticated methods of analysis are being studied. Huang et al studied head and neck cancer xenograft response evaluation at the William Beaumont Hospital Micro-PET facility, comparing SUV, retention index, and kinetic index, defined by Patlak analysis. Findings were correlated with histologic analysis of xenograft specimens in 30 mice who underwent 27 successful images. Kinetic index (10-30 min) and retention index (30-60 min) were the optimal parameters for radiation necrosis among responding tumors. SUV (30 min) excelled at predicting late radiation necrosis among recurring tumors. Dynamic parameters were found to be more predictive of early radiation change, and static parameters correlated with final tumor status.39
Conclusions Technical innovations allow us to administer radiotherapy in a manner that significantly improves patients’ quality of life after head and neck irradiation, while leading to at least comparable or improved locoregional control. FDG-PET/CT has proven its value for volume definition, response evaluation, and risk adaptive treatment modification. Remaining technical hurdles include threshold definition and scanner resolution. New probes for hypoxia, apoptosis, and cellular proliferation will certainly refine its role for the near future.
References 1. Chao KS, Deasy JO, Markman J, et al: A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: Initial results. Int J Radiat Oncol Biol Phys 2001;49:907-916 2. Eisbruch A, Haken RK, Kim HM, et al: Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 1999;45:577-587 3. Tsien C, Eisbruch A, McShan D, et al: Intensity-modulated radiation therapy (IMRT) for locally advanced paranasal sinus tumors: Incorporating clinical decisions in the optimization process. Int J Radiat Oncol Biol Phys 2003;55:776-784 4. Eisbruch A, Schwartz M, Rasch C, et al: Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: Which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys 2004;60:1425-1439 5. Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized intergroup study 0099. J Clin Oncol 1998;16:1310-1317
M.K. Garg, J. Glanzman, and S. Kalnicki 6. Emami B, Lyman J, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-122 7. Soto DE, Kessler ML, Piert M, et al: Correlation between pretreatment FDG-PET biological target volume and anatomical location of failure after radiation therapy for head and neck cancers. Radiother Oncol 2008;89:13-18 8. Conti PS, Lilien DL, Hawley K, et al: PET and [18F]-FDG in oncology: A clinical update. Nucl Med Biol 1996;23:717-735 9. Di Martino E, Nowak B, Hassan HA, et al: Diagnosis and staging of head and neck cancer: A comparison of modern imaging modalities (positron emission tomography, computed tomography, color-coded duplex sonography) with panendoscopic and histopathologic findings. Arch Otolaryngol Head Neck Surg 2000;126:1457-1461 10. Johansen J, Eigtved A, Buchwald C, et al: Implication of 18F-fluoro-2deoxy-D-glucose positron emission tomography on management of carcinoma of unknown primary in the head and neck: A Danish cohort study. Laryngoscope 2002;112:2009-2014 11. Schöder H, Yeung HW, Gonen M, et al: Head and neck cancer: Clinical usefulness and accuracy of PET/CT image fusion. Radiology 2004;231: 65-72 12. Goerres GW, von Schulthess GK, Steinert HC: Why most PET of lung and head-and-neck cancer will be PET/CT. J Nucl Med 2004;45:66S71S 13. Schwartz DL, Ford E, Rajendran J, et al: FDG-PET/CT imaging for preradiotherapy staging of head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2005;61:129-136 14. Daisne JF, Duprez T, Weynand B, et al: Tumor volume in pharyngolaryngeal squamous cell carcinoma: Comparison at CT, MR imaging, and FDG PET and validation with surgical specimen. Radiology 2004;233: 93-100 15. Nishioka T, Shiga T, Shirato H, et al: Image fusion between 18FDG-PET and MRI/CT for radiotherapy planning of oropharyngeal and nasopharyngeal carcinomas. Int J Radiat Oncol Biol Phys 2002;53:1051-1057 16. Ciernik IF, Dizendorf E, Baumert BG, et al: Radiation treatment planning with an integrated positron emission and computer tomography (PET/CT): A feasibility study. Int J Radiat Oncol Biol Phys 2003;57: 853-863 17. Heron DE, Andrade RS, Flickinger J, et al: Hybrid PET-CT simulation for radiation treatment planning in head-and-neck cancers: A brief technical report. Int J Radiat Oncol Biol Phys 2004;60:1419-1424 18. Paulino AC, Koshy M, Howell R, et al: Comparison of CT- and FDGPET-defined gross tumor volume in intensity-modulated radiotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2005;61:13851392 19. Riegel AC, Berson AM, Destian S, et al: Variability of gross tumor volume delineation in head-and-neck cancer using CT and PET/CT fusion. Int J Radiat Oncol Biol Phys 2006;65:726-732 20. El-Bassiouni M, Ciernik IF, Davis JB, et al: [18FDG] PET-CT-based intensity-modulated radiotherapy treatment planning of head and neck cancer. Int J Radiat Oncol Biol Phys 2007;69:286-293 21. Wang D, Schultz CJ, Jursinic PA, et al: Initial experience of FDGPET/CT guided IMRT of head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2006;65:143-151 22. Ahn PH, Mehta K, Mutyala S, et al: PET-CT for target delineation for definitive radiotherapy in head and neck cancers: The Montefiore/Albert Einstein experience. Presented at: 2007 ACNP Meeting; February 2007, SanAntonio, TX 23. Ashamalla H, Guirgius A, Bieniek E, et al: The impact of positron emission tomography/computed tomography in edge delineation of gross tumor volume for head and neck cancers. Int J Radiat Oncol Biol Phys 2007;68:388-395 24. Rajendran JG, Hendrickson KR, Spence AM, et al: Hypoxia imaging directed radiation treatment planning. Eur J Nucl Med Mol Imaging 2006;33:S44-S53 25. Overgaard J, Hansen HS, Overgaard M, et al: A randomized doubleblind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) protocol 5-85. Radiother Oncol 1998;46:135-146
The evolving role of PET/CT in organ-preserving treatment of head and neck cancer 26. Serganova I, Blasberg R: Reporter gene imaging: Potential impact on therapy. Nucl Med Biol 2005;32:763-780 27. Grosu AL, Souvatzoglou M, Röper B, 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;69:541-551 28. Lehtiö K, Eskola O, Viljanen T, et al: Imaging perfusion and hypoxia with PET to predict radiotherapy response in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2004;59:971-982 29. Juweid ME, Cheson BD: Positron-emission tomography and assessment of cancer therapy. N Engl J Med 2006;354:496-507 30. Andrade RS, Heron DE, Degirmenci B, et al: Posttreatment assessment of response using FDG-PET/CT for patients treated with definitive radiation therapy for head and neck cancers. Int J Radiat Oncol Biol Phys 2006;65:1315-1322 31. Yao M, Graham MM, Hoffman HT, et al: The role of post-radiation therapy FDG PET in prediction of necessity for post-radiation therapy neck dissection in locally advanced head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2004;59:1001-1010 32. Zundel MT, Michel MA, Schultz CJ, et al: Comparison of physical examination and fluorodeoxyglucose positron emission tomography/ computed tomography 4-6 months after radiotherapy to assess residual head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011;81: e825-e832
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33. Brun E, Kjellén E, Tennvall J, et al: FDG PET studies during treatment: Prediction of therapy outcome in head and neck squamous cell carcinoma. Head Neck 2002;24:127-135 34. Yao M, Smith RB, Graham MM, et al: The role of FDG PET in management of neck metastasis from head-and-neck cancer after definitive radiation treatment. Int J Radiat Oncol Biol Phys 2005;63:991-999 35. Yao M, Graham MM, Smith RB, et al: Value of FDG PET in assessment of treatment response and surveillance in head-and-neck cancer patients after intensity modulated radiation treatment: A preliminary report. Int J Radiat Oncol Biol Phys 2004;60:1410-1418 36. Passero VA, Branstetter BF, Shuai Y, et al: Response assessment by combined PET-CT scan versus CT scan alone using RECIST in patients with locally advanced head and neck cancer treated with chemoradiotherapy. Ann Oncol 2010;21:2278-2283 37. Murphy JD, La TH, Chu K, et al: Postradiation metabolic tumor volume predicts outcome in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011;80:514-521 38. Tang C, Murphy J, Khong B, et al: Validation that metabolic tumor volume predicts outcome in head-and-neck cancer. Int J Radiat Oncol Biol Phys e-pub ahead of print, 2011 39. Huang J, Chunta J, Amin M, et al: Detailed characterization of the early response of head–neck cancer xenografts to Irradiation using 18F-FDGPET imaging. Int J Radiat Oncol Biol Phys 2012 Feb 11 [Epub ahead of print]
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ositron emission tomography (PET)/computed tomography (CT) has emerged as an essential tool in the management of squamous cell carcinomas of the head and neck; it plays a key role in diagnosis, staging, and response evaluation, and it has gained tremendous relevance in radiation treatment. In fact, the biological complexity of head and neck cancers, the multiple structures it can invade, and the sparing of essential normal tissues to decrease morbidity make PET/CT a major addition to our therapeutic armamentarium. The recent development of intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy has resulted in such radiation dose conformality that the radiation oncologist can address the target tumor with higher radiobiological effectiveness while leading to increased normal tissue sparing (Fig. 1). This translates into im-
Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY. Address reprint requests to Shalom Kalnicki, MD, Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467-2401. E-mail: skalnick@ montefiore.org.
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proved local control rates with decreased treatment-related morbidity. Especially in cancers of the head and neck, where the confluence of small normal structures within a complex anatomical region makes conventional radiation extremely toxic, IMRT driven “dose sculpting” has decreased the morbidities of radiation therapy, notably xerostomia, osteoradionecrosis, and swallowing dysfunction, with significant improvement of quality of life.1-4 In addition, the simultaneous administration of chemotherapy and radiation, although leading to improved local control and survival in locally advanced head and neck cancers, amplifies morbidities to such an extent that before the IMRT era many patients did not complete therapy; these new techniques have changed this scenario dramatically.5 Improved results with radiation treatment, especially associated with chemotherapy, have thus heralded the era of organ preservation in head and neck cancer. Organ preservation requires relatively high doses of radiation (66-72 Gy in 33-39 daily fractions or 74-82 Gy in 62-68 fractions twice per day) to the gross tumor in the primary site and areas of gross nodal metastases. In the postoperative setting for high-risk
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Figure 1 An example of a head and neck intensity-modulated radiation therapy (IMRT) plan and field arrangement with multiple beams, allowing for improved dose conformality.
patients (ie, extracapsular nodal extension, close margins), the tumor bed and nodal areas will often be treated to a dose of 66-72 Gy delivered in 33-39 treatment sessions. Normal tissue tolerance to radiation treatment is dependent on the tissue being treated, the volume of tissue irradiated, and sensitizing agents, such as chemotherapy.6 In head and neck IMRT irradiation, the parotid glands are commonly constrained to a mean dose of 26 Gy, spinal cord dose is almost invariably kept below 45 Gy, the mandible below 70 Gy, and the superior pharyngeal constrictor muscles have a maximum tolerable dose of 45 Gy. It becomes immediately obvious how the normal tissue tolerance doses are significantly lower than the tumor target doses outlined previously and by the proximity of these normal tissues to the tumor harboring structures (Fig. 2). It is thus essential to define radiation volumes that are both necessary and sufficient for proper dose delivery. Inadequate coverage to tumor and nodal targets with their proper dose (geographic miss) would dramatically increase the propensity for locoregional and subsequent distant failure. Excessive expansion of target volumes will produce dose deposition in normal tissues and severely increase treatment morbidity. Establishing and contouring the exact target volumes is the major determinant of outcome; the gross tumor volume (GTV) is established with imaging and clinical examination; the clinical target volume consists of nodal areas or anatomical compartments that are known to be at risk for microscopic involvement; finally, the planning target volume (PTV) includes a three-dimensional expansion to account for daily treatment setup inaccuracies. To these traditional definitions, some authors now add the concept of biological target volume as determined by PET/CT.7
PET/CT in Radiation Planning The sensitivity of anatomically based imaging for head and neck cancer at the primary site is less than ideal, with 50%95% for CT and 68%-92% for magnetic resonance imaging (MRI). Bulky nodal involvement in the neck is easily detected clinically, but for smaller and intermediate-sized nodes, the sensitivity of CT for metastases is 65%-95%, whereas for MRI is 35%-90%. For both modalities, specificity is a function of size. PET/CT with 18F-fluorodeoxyglucose (FDG) is useful for determining tumor location, stage, persistence, and recurrence in head and neck cancer. Its usage has been increasing secondary to its high sensitivity (90%-96%) at the primary site and high sensitivity (85%-90%) and specificity (70%95%) in nodal areas8,9 (Fig. 3). It is especially valuable in detection of primary site in tumors that manifest itself as nodal metastasis without a clinically evident primary site.10 In preradiation scanning, PET/CT is accepted as significantly superior to PET alone in identification of areas of tumor involvement11,12 with a sensitivity of 96% and specificity of 98.5%.13 There is abundant evidence supporting the routine use of PET/CT in targeting head and neck cancers with radiation. Daisne et al14 compared CT-, MRI-, and PET-delineated volumes in 29 patients with oropharyngeal, hypopharyngeal, or laryngeal tumors, including analysis of surgical specimens in 9 patients who underwent a total laryngectomy; nodal volumes were not outlined. Surgical specimen was significantly smaller compared with all 3 imaging modalities (CT ⫽ 20.8 cm3, MRI ⫽ 23.8 cm3, PET ⫽ 16.3 cm3, surgical specimen ⫽ 12.6 cm3). PET volumes were significantly smaller than the other 2 imaging modalities. Most strikingly, no imaging mo-
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Figure 2 In this head and neck IMRT plan, one can see the dose sculpting and organ preservation that IMRT creates. (A and B) Organ preservation of larynx and left parotid. (C) An example of dose volume histograms.
dality fully represented superficial extent of tumor, with underestimation of superficial tumor extension in the mucosa of the contralateral larynx and extralaryngeal extension. Nishioka et al15 performed FDG-PET and MRI or CT in treatment planning position in 21 patients, 19 of which did not have a significant change in delineated volumes between treatment modalities; 4 patients had an increase in nodal staging, completely changing their target volumes and therapeutic approach. The feasibility of coregistering PET/CT data into computerized radiation therapy planning systems became evident more than a decade ago. Ciernik et al16 successfully coregistered PET/CT with noncontrast treatment planning CT in 12 patients, noting 50% change in GTV of 25% of greater on PET/CT compared with CT alone. Four patients had a decrease in GTV of 10% or more on PET/CT, and 16% of these patients were found to have distant metastases on initial staging PET/CT, eliminating ineffective local treatment in 25% of patients studied. Heron et al17 conducted one of the first systematic comparative reviews between volumes delineated with contrast CT alone versus PET/CT-derived targets. The authors found volumes of primary disease delineated on CT
to be up to 3-fold larger than volumes delineated on PET/CT. This statistically significant finding may be skewed by 1 patient with carcinoma of the base of tongue in which the CT volume was 23 times larger than the PET/CT volume. In addition, in 1 patient with carcinoma of the oral tongue, the CT volume was 9.5-fold larger than the PET/CT volume. It is unclear what role any streak artifacts from dental implants may have played in the wide variability between CT and PET/CT volumes in these 2 patients. There was no statistically significant difference in nodal volumes outlined between CT and PET/CT. PET/CT also influenced treatment management, as additional 3 patients were found to have nodal metastatic disease. Similar results were reported by Paulino et al18 who found that tumor size decreased when delineated by PET/CT in 30/40 patients, whereas 7/40 had an increase in size; median GTV on PET is smaller than on CT (37 vs 20.3 cm3). Similar results were obtained by several other authors.19-21 In our institution, Ahn and colleagues22 analyzed 46 patients for CT alone versus PET/CT volume differences in both the primary site and the neck; 21% of patients had an increase in the number of nodes detected on PET/CT compared
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volume dose for microscopic disease into GTV dose for gross disease. The importance of this added dose could not be overemphasized, as it may lead to improved outcomes. Accounting for differences in volumes and doses, the authors estimated that the addition of PET/CT to CT alone changed radiation planning in approximately 55% of patients.
Issues and Controversies Interobserver variability in outlining the radiation target volumes is a matter of high importance in modern radiation oncology, affecting clinical trials and outcomes reporting. The use of PET/CT can decrease this variability by adding an additional parameter with standardized volumes. In the study of Ciernik et al,16 the use of PET/CT significantly de-
Figure 3 In this postoperative squamous cell carcinoma of the anterior tongue, persistent/recurrent disease was noted on positron emission tomography (PET) but not visualized on postoperative computed tomography (CT).
with CT (Fig. 4), whereas 14% had a decrease in the number of nodes detected on CT; 23% of patients had a larger volume (110%) drawn on PET/CT than on CT, whereas 54% of patients had a smaller volume (90%) delineated on PET/CT than on CT (Fig. 5). In general, PET/CT volumes of the primary lesions tend to be smaller than CT ones, as one clearly separates inflammatory mucosal and submucosal components of the mass lesion; in a smaller number of cases, especially base of tongue, PET/CT adds volume by identifying disease lying within or adjacent to muscle layers and infiltrative neoplastic processes, which appear normal on CT (Fig. 6). For nodal disease, there is little volume variability but PET/CT adds value by identifying abnormal uptake in nodes that appear normal on CT by volume only (⬍1 cm). In this case, there is a change in the patient’s tumor, nodes, metastases staging, leading to a transformation of clinical target
Figure 4 In this patient with base of tongue carcinoma, a right fluorodeoxyglucose avid node is detected on PET/CT, not easily visualized on CT alone.
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M.K. Garg, J. Glanzman, and S. Kalnicki (SUV) value as determined by PET phantom, 50% isointensity level, and others. A popular technique has been fixed threshold of the background-subtracted tumor maximum uptake, usually 40%-50%. Ashamalla et al23 have suggested inclusion of the “halo” of the PET-avid mass. FDG-PET in its current form is not an extremely accurate test, with a spatial resolution of approximately 0.4-0.7 cm. This is dependent both on the intrinsic physical properties of the scanner, as well as the distance traveled by the positron from the 18F-moiety of FDG before photon– electron pair annihilation. The magnitude of the spatial resolution uncertainty is considered to be a function of tumor size. In radiation oncology planning, the portion of the GTV expansion to generate PTV includes margin to account for microscopic extension of the tumor, which may not be evident on imaging. At our institution, common practice in the head and neck is to have a 0.5-cm expansion on GTV in the PTV to account for this microscopic extension, with a further 0.5-cm expansion to account for setup error or patient movement. In this case, considering that the most likely spatial resolution error would be 0.5 cm, for a worst-case scenario, the delineated tumor in one dimension could be overestimated by 1 cm. At the other extreme, there would be enough margins to account for setup error with a 0.5 cm GTV to PTV expansion.
Non-FDG-PET Probes
Figure 5 In this patient with base of tongue carcinoma, an example of the PET avid volume being smaller than the gross tumor volume (GTV) delineated on CT alone.
creased the mean volume difference between 2 contouring radiation oncologists by a multiple of 4 or 17 cm3. This observation appears to conflict with the findings of Riegel et al19 and is likely because of a standardized threshold algorithm used by Ciernik. When delineating tumor on PET, selection of the threshold algorithm can lead to large differences in outlined volume. The issue of threshold determination is controversial, and investigators have used several different techniques. This varies between arbitrary threshold levels, liver uptake normalization, 50% of maximal standardized uptake value
Hypoxia PET markers are of potential great interest in radiation treatment planning.24 Chronically hypoxic cells are relatively radioresistant because they lack sufficient oxygen for fixation of free radical damage and consequent apoptosis. These areas can be detected using markers conjugated to misonidazole, tirapazamine, and other agents that act via the inherent affinity of these molecules for electron-rich reductive states. These hypoxic areas are candidates to receive radiation doses of 70 Gy or more. Because of this property, these agents also act as hypoxic cell sensitizers by causing fixation of radiation-induced damage in a manner similar to that of oxygen. Trials of hypoxia markers as radiation sensitizers have been largely negative, with the notable exception of nimorazole in a subset of patients with pharyngeal and supraglottic larynx tumors.25 Additional imaging strategies with reporter gene imaging may potentially have utility in identifying areas of tumor spread26 and in their radiotherapy targeting with an 18F-fluoroazomycinarabinoside marker.27 Tumor flow and oxygenation are essential for radiation response. Lehtio et al28 measured oxygenation status using 18F-fluoroerythronitroimidazole in addition to standard FDG PET to determine the fractional hypoxic volume and tumor blood flow. In a study of 21 patients, the ones with fractional hypoxic volume greater than the median had significantly worse local control and survival, pointing toward the importance of establishing the presence and location of hypoxia.28 In our institution, we are studying the potential implications of an 2-(5-fluoro-pentyl)-2-methyl-malonic acid, [18F]ML-10 apoptosis marker in early response evaluation of patients undergoing head and neck cancer chemo-irradiation.
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Figure 6 The use of PET in a 45-year-old male patient with a locally advanced supraglottic tumor treated to a dose of 70 Gy. The PET/CT was fused with the treatment planning CT. PET allows for the sparing of essential normal tissue and organ preservation in head and neck cancer while allowing for the identification and contouring of exact tumor volumes with a sensitivity of 90%-96% at the primary site. A smaller more precise GTV for the primary lesion is defined with the use of PET, whereas a CT alone cannot differentiate between inflammatory mucosal and submucosal components and would lead to GTV overestimation. Arrow signifies GTV after PET fusion.
Response Evaluation and Risk Adaptive Therapy The use of PET as a noninvasive surrogate for assessing response to therapy with organ-sparing chemoradiation is currently being assessed. Restaging through PET for restaging yields a sensitivity of approximately 80%-95%, a specificity of 75%-90%, and an accuracy of 80%-90%. In a study of 28 head and neck patients, PET/CT performed 8 weeks after definitive radiotherapy had a sensitivity of 77% and specificity of 93%, in comparison with a sensitivity and specificity of 86% and 58% for contrast-enhanced CT.29-30 A series of 12 patients with a clinically palpable residual neck mass found that PET/CT was highly accurate in the determination of residual tumor.31 Time-honored assessment methods rely heavily on physical examination, as imaging techniques have been lacking. At the University of Winsconsin, Zundel et al32 compared posttreatment PET/CT with physical examination for detection of locoregional failures, finding a sensitivity of 100% versus 50% and specificities of 64.6% versus 89.6%, establishing that a negative PET/CT after therapy is much more indicative of local control than a negative physical examination. Brun et al studied 47 patients with stage II-IV squamous cell carcinomas with 2 PET/CT examinations, one before and one 1-3 weeks after definitive treatment; metabolic rate (MR) and SUV were measured. After a median follow-up time of 3.3 years, the authors found that lower metabolic rate and SUV were significantly associated with complete response.33 At the University of Iowa, Yao et al31 reported on 12 patients who underwent neck dissections for residual lymphadenopathy after irradiation. All patients with a negative or maximum nodal SUV ⬍3 postradiation PET had a negative neck dissection; hence, a neck dissection can be avoided on basis of the postradiation PET scan. Deploying that strategy
on a larger sample of 53 patients, with 70 heminecks available for analysis, the authors concluded that neck dissection can be safely omitted in patients with small residual adenopathy on CT but with a negative PET 12 weeks after irradiation.34 The same group studied 64 patients who had a negative first PET/CT after treatment; 40 remained locoregionally controlled, whereas 3 developed distant metastasis; only 1 of 45 patients with an initially negative study developed local recurrence; none of 49 patients with a negative neck on PET/CT developed a neck recurrence, making a negative PET an excellent marker for nodal disease control. Six of 11 patients with positive posttreatment studies at the primary site had persistent disease, allowing for salvage surgery to be deployed in a timely fashion.35 The University of Pittsburgh group used its early experience in PET radiation planning to analyze timing and sensitivity of response evaluation after therapy. Andrade et al found a sensitivity of 76.9% and specificity of 93.3% for PET/CT scans 8 weeks after completing therapy in the first series of 28 patients.30 Passero et al analyzed 53 patients with previously untreated stages III-IVb disease, treated with primary concurrent chemoradiotherapy. Response was assessed by clinical examination, CT, and PET portions of combined PET/CT scan approximately 8 weeks after completion of treatment. Complete response (CR) rates were clinical examination ⫽ 42/53 (79%), CT ⫽ 15/53 (28%), and PET/CT ⫽ 27/53 (51%). On statistical analysis, CR as assessed by PET, but not as assessed by clinical examination or CT using response criteria evaluation for solid tumors criteria, correlated significantly with progression-free status (P ⬍ 0.0001). The 2-year progression-free survival for patients with CR and without CR by PET was 93% and 48%, respectively (P ⫽ 0.0002). A negative PET scan on combined PET/CT after chemoradiotherapy is a powerful predictor of outcome, and
326 PET/CT significantly improved the accuracy of posttreatment assessment by CT.36 As always, standardizing what uptake could be identified with recurrent or persistent disease is a controversial point. The Stanford group performed a detailed analysis of 47 patients who underwent posttreatment PET, applying Cox regression models to different levels of uptake. They found a highly significant statistical correlation with the metabolic tumor volume above 2.0. An increase in metabolic tumor volume above 2.0 represented hazard ratios of approximately 2.1 for disease-free survival and 2.0 for overall survival after chemoirradiation for head and neck cancer.37 The group further validated their findings for human papillomavirus-positive and -negative head and neck cancers, in a study of 83 patients.38 Other sophisticated methods of analysis are being studied. Huang et al studied head and neck cancer xenograft response evaluation at the William Beaumont Hospital Micro-PET facility, comparing SUV, retention index, and kinetic index, defined by Patlak analysis. Findings were correlated with histologic analysis of xenograft specimens in 30 mice who underwent 27 successful images. Kinetic index (10-30 min) and retention index (30-60 min) were the optimal parameters for radiation necrosis among responding tumors. SUV (30 min) excelled at predicting late radiation necrosis among recurring tumors. Dynamic parameters were found to be more predictive of early radiation change, and static parameters correlated with final tumor status.39
Conclusions Technical innovations allow us to administer radiotherapy in a manner that significantly improves patients’ quality of life after head and neck irradiation, while leading to at least comparable or improved locoregional control. FDG-PET/CT has proven its value for volume definition, response evaluation, and risk adaptive treatment modification. Remaining technical hurdles include threshold definition and scanner resolution. New probes for hypoxia, apoptosis, and cellular proliferation will certainly refine its role for the near future.
References 1. Chao KS, Deasy JO, Markman J, et al: A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: Initial results. Int J Radiat Oncol Biol Phys 2001;49:907-916 2. Eisbruch A, Haken RK, Kim HM, et al: Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 1999;45:577-587 3. Tsien C, Eisbruch A, McShan D, et al: Intensity-modulated radiation therapy (IMRT) for locally advanced paranasal sinus tumors: Incorporating clinical decisions in the optimization process. Int J Radiat Oncol Biol Phys 2003;55:776-784 4. Eisbruch A, Schwartz M, Rasch C, et al: Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: Which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys 2004;60:1425-1439 5. Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized intergroup study 0099. J Clin Oncol 1998;16:1310-1317
M.K. Garg, J. Glanzman, and S. Kalnicki 6. Emami B, Lyman J, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-122 7. Soto DE, Kessler ML, Piert M, et al: Correlation between pretreatment FDG-PET biological target volume and anatomical location of failure after radiation therapy for head and neck cancers. Radiother Oncol 2008;89:13-18 8. Conti PS, Lilien DL, Hawley K, et al: PET and [18F]-FDG in oncology: A clinical update. Nucl Med Biol 1996;23:717-735 9. Di Martino E, Nowak B, Hassan HA, et al: Diagnosis and staging of head and neck cancer: A comparison of modern imaging modalities (positron emission tomography, computed tomography, color-coded duplex sonography) with panendoscopic and histopathologic findings. Arch Otolaryngol Head Neck Surg 2000;126:1457-1461 10. Johansen J, Eigtved A, Buchwald C, et al: Implication of 18F-fluoro-2deoxy-D-glucose positron emission tomography on management of carcinoma of unknown primary in the head and neck: A Danish cohort study. Laryngoscope 2002;112:2009-2014 11. Schöder H, Yeung HW, Gonen M, et al: Head and neck cancer: Clinical usefulness and accuracy of PET/CT image fusion. Radiology 2004;231: 65-72 12. Goerres GW, von Schulthess GK, Steinert HC: Why most PET of lung and head-and-neck cancer will be PET/CT. J Nucl Med 2004;45:66S71S 13. Schwartz DL, Ford E, Rajendran J, et al: FDG-PET/CT imaging for preradiotherapy staging of head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2005;61:129-136 14. Daisne JF, Duprez T, Weynand B, et al: Tumor volume in pharyngolaryngeal squamous cell carcinoma: Comparison at CT, MR imaging, and FDG PET and validation with surgical specimen. Radiology 2004;233: 93-100 15. Nishioka T, Shiga T, Shirato H, et al: Image fusion between 18FDG-PET and MRI/CT for radiotherapy planning of oropharyngeal and nasopharyngeal carcinomas. Int J Radiat Oncol Biol Phys 2002;53:1051-1057 16. Ciernik IF, Dizendorf E, Baumert BG, et al: Radiation treatment planning with an integrated positron emission and computer tomography (PET/CT): A feasibility study. Int J Radiat Oncol Biol Phys 2003;57: 853-863 17. Heron DE, Andrade RS, Flickinger J, et al: Hybrid PET-CT simulation for radiation treatment planning in head-and-neck cancers: A brief technical report. Int J Radiat Oncol Biol Phys 2004;60:1419-1424 18. Paulino AC, Koshy M, Howell R, et al: Comparison of CT- and FDGPET-defined gross tumor volume in intensity-modulated radiotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2005;61:13851392 19. Riegel AC, Berson AM, Destian S, et al: Variability of gross tumor volume delineation in head-and-neck cancer using CT and PET/CT fusion. Int J Radiat Oncol Biol Phys 2006;65:726-732 20. El-Bassiouni M, Ciernik IF, Davis JB, et al: [18FDG] PET-CT-based intensity-modulated radiotherapy treatment planning of head and neck cancer. Int J Radiat Oncol Biol Phys 2007;69:286-293 21. Wang D, Schultz CJ, Jursinic PA, et al: Initial experience of FDGPET/CT guided IMRT of head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2006;65:143-151 22. Ahn PH, Mehta K, Mutyala S, et al: PET-CT for target delineation for definitive radiotherapy in head and neck cancers: The Montefiore/Albert Einstein experience. Presented at: 2007 ACNP Meeting; February 2007, SanAntonio, TX 23. Ashamalla H, Guirgius A, Bieniek E, et al: The impact of positron emission tomography/computed tomography in edge delineation of gross tumor volume for head and neck cancers. Int J Radiat Oncol Biol Phys 2007;68:388-395 24. Rajendran JG, Hendrickson KR, Spence AM, et al: Hypoxia imaging directed radiation treatment planning. Eur J Nucl Med Mol Imaging 2006;33:S44-S53 25. Overgaard J, Hansen HS, Overgaard M, et al: A randomized doubleblind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) protocol 5-85. Radiother Oncol 1998;46:135-146
The evolving role of PET/CT in organ-preserving treatment of head and neck cancer 26. Serganova I, Blasberg R: Reporter gene imaging: Potential impact on therapy. Nucl Med Biol 2005;32:763-780 27. Grosu AL, Souvatzoglou M, Röper B, 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;69:541-551 28. Lehtiö K, Eskola O, Viljanen T, et al: Imaging perfusion and hypoxia with PET to predict radiotherapy response in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2004;59:971-982 29. Juweid ME, Cheson BD: Positron-emission tomography and assessment of cancer therapy. N Engl J Med 2006;354:496-507 30. Andrade RS, Heron DE, Degirmenci B, et al: Posttreatment assessment of response using FDG-PET/CT for patients treated with definitive radiation therapy for head and neck cancers. Int J Radiat Oncol Biol Phys 2006;65:1315-1322 31. Yao M, Graham MM, Hoffman HT, et al: The role of post-radiation therapy FDG PET in prediction of necessity for post-radiation therapy neck dissection in locally advanced head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2004;59:1001-1010 32. Zundel MT, Michel MA, Schultz CJ, et al: Comparison of physical examination and fluorodeoxyglucose positron emission tomography/ computed tomography 4-6 months after radiotherapy to assess residual head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011;81: e825-e832
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33. Brun E, Kjellén E, Tennvall J, et al: FDG PET studies during treatment: Prediction of therapy outcome in head and neck squamous cell carcinoma. Head Neck 2002;24:127-135 34. Yao M, Smith RB, Graham MM, et al: The role of FDG PET in management of neck metastasis from head-and-neck cancer after definitive radiation treatment. Int J Radiat Oncol Biol Phys 2005;63:991-999 35. Yao M, Graham MM, Smith RB, et al: Value of FDG PET in assessment of treatment response and surveillance in head-and-neck cancer patients after intensity modulated radiation treatment: A preliminary report. Int J Radiat Oncol Biol Phys 2004;60:1410-1418 36. Passero VA, Branstetter BF, Shuai Y, et al: Response assessment by combined PET-CT scan versus CT scan alone using RECIST in patients with locally advanced head and neck cancer treated with chemoradiotherapy. Ann Oncol 2010;21:2278-2283 37. Murphy JD, La TH, Chu K, et al: Postradiation metabolic tumor volume predicts outcome in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011;80:514-521 38. Tang C, Murphy J, Khong B, et al: Validation that metabolic tumor volume predicts outcome in head-and-neck cancer. Int J Radiat Oncol Biol Phys e-pub ahead of print, 2011 39. Huang J, Chunta J, Amin M, et al: Detailed characterization of the early response of head–neck cancer xenografts to Irradiation using 18F-FDGPET imaging. Int J Radiat Oncol Biol Phys 2012 Feb 11 [Epub ahead of print]