|Year : 2010 | Volume
| Issue : 3 | Page : 260-266
Challenges in integrating 18FDG PET-CT into radiotherapy planning of head and neck cancer
P Dandekar1, M Partridge2, R Kazi3, C Nutting3, K Harrington3, K Newbold1
1 Head and Neck Unit, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, United Kingdom
2 Joint Department of Physics, The Institute of Cancer Research, Downs Road, SM2 5PT, United Kingdom
3 Head and Neck Unit, The Royal Marsden NHS Foundation trust, Granard House, Fulham Road, SW3 6JJ, London, United Kingdom
|Date of Web Publication||28-Jun-2010|
Head and Neck Unit, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT
Source of Support: None, Conflict of Interest: None
Radiotherapy forms one of the major treatment modalities for head and neck cancers (HNC), and precision radiotherapy techniques, such as intensity-modulated radiotherapy require accurate target delineation to ensure success of the treatment. Conventionally used imaging modalities, such as X-ray computed tomography (CT) and magnetic resonance imaging are used to delineate the tumor. Imaging, such as positron emission tomography (PET)-CT, which combines the functional and anatomic modalities, is increasingly being used in the management of HNC. Currently, 18-fluorodeoxyglucose is the most commonly used radioisotope, which is accumulated in areas of high glucose uptake, such as the tumor tissue. Because most disease recurrences are within the high-dose radiotherapy volume, defining a biological target volume for radiotherapy boost is an attractive approach to improve the results. There are many challenges in employing the PET-CT for radiotherapy planning, such as patient positioning, target edge definition, and use of new PET tracers, which represent various functional properties, such as hypoxia, protein synthesis, and proliferation. The role of PET-CT for radiotherapy planning is ever expanding and more clinical data underlining the advantages and challenges in this approach are emerging. In this article, we review the current clinical evidence for the application of functional imaging to radiotherapy planning and discuss some of the current challenges and possible solutions that have been suggested to date.
Keywords: PET-CT, functional imaging, biologically targeted radiotherapy, radiotherapy, adaptive radiotherapy
|How to cite this article:|
Dandekar P, Partridge M, Kazi R, Nutting C, Harrington K, Newbold K. Challenges in integrating 18FDG PET-CT into radiotherapy planning of head and neck cancer. Indian J Cancer 2010;47:260-6
|How to cite this URL:|
Dandekar P, Partridge M, Kazi R, Nutting C, Harrington K, Newbold K. Challenges in integrating 18FDG PET-CT into radiotherapy planning of head and neck cancer. Indian J Cancer [serial online] 2010 [cited 2019 Dec 15];47:260-6. Available from: http://www.indianjcancer.com/text.asp?2010/47/3/260/64717
| » Introduction|| |
Radiotherapy is an integral part of treatment for head and neck cancer (HNC). It has evolved from orthovoltage X-ray machines to state-of-the-art linear accelerators with megavoltage radiation. In addition, radiotherapy treatment delivery techniques have developed from conventional open field treatment to precision techniques, such as intensity-modulated radiation therapy (IMRT). These precision radiotherapy techniques have improved the tumor coverage as well as limited the excessive dose to the organs at risk (OAR), thus improving the therapeutic ratio. In spite of the technologic advances in radiotherapy delivery, results for advanced HNC are still disappointing. The possible reasons for the failure of radiotherapy could be radioresistance of the tumor, inadequate dose to target volume due to proximity to critical structures, or geographic miss. Conventionally, X-ray computed tomography (CT) has been used to delineate target volumes as well as OAR and new functional imaging modalities, such as positron emission tomography (PET) promises to improve the target definition by defining a metabolically active biological target volume (BTV).
| » Anatomic Imaging|| |
The primary step in radiotherapy planning is to define target volumes and OAR using imaging to identify local, regional, and distant extent of the disease. Ideally, an imaging modality with a sensitivity and specificity of 100% should be employed to define the radiotherapy volumes, but such precision has yet to be achieved. Anatomic imaging, such as CT and magnetic resonance imaging (MRI), remain the most widely used modalities for target delineation. The conventional MRI protocols, such as T 1 -weighted and T 2 -weighted, are more accurate in soft tissue delineation than CT, especially for lesions involving the tongue or nasopharynx.  CT is essential in radiotherapy planning as the planning algorithms use the CT data to create an electron density map for dose calculation. Therefore, MRI or PET alone cannot be used for radiotherapy planning and require fusion with CT. One of the main limitations of CT is that it represents anatomic information regardless of the biological changes in the tissues making differentiation of benign processes that cause a change in the shape or size of a structure from a true malignant process difficult. CT is also affected by the artifacts from dense materials, such as dental fillings or prosthetic replacement joints, which can obscure the view of the anatomy and pathology in the proximity. These shortcomings can lead to a failure of accurate delineation of the disease and could result in an inadequate dose to the tumor and failure to control the disease.
| » Positron Emission Tomography and Isotopes|| |
The role of PET in oncology is well established specifically for diagnosis in various tumor types, such as head and neck, lymphoma, lung, and colorectal. The most commonly used PET radioisotope is 18 F-fluorodeoxyglucose ( 18 F-FDG), which has a specific high affinity for areas of high glucose metabolism, present in malignant lesions. Tumor tissues have increased concentrations of the transmembrane glucose transporters and actively concentrate 18 F-FDG in comparison with most healthy tissues. Unlike normal glucose, 18 FDG is trapped in the cells after undergoing phosphorylation by hexokinase and is unable to proceed with glycolysis. The trapped 18 F decays by positron emission, and the positron then annihilates to produce 2 photons in exactly opposite directions, which are detected by the scanner, producing a 3-dimensional image. The tumor tissues frequently take up 18 F-FDG, but this effect is not exclusive since physiologic uptake of 18 F-FDG is seen in the brain, heart, laryngeal muscles, brown fat, urinary bladder, and inflammatory tissue. The uptake of 18 F-FDG is influenced by various factors, such as tumor blood flow, activity of glucose transporters and hexokinase, and by glucose consumption.
Other isotopes specific to various physiologic processes are available but currently limited to the research arena, such as carbon-11, oxygen-15, and nitrogen-13. Apart from high glucose metabolism, the tumor tissues also exhibit high levels of protein synthesis and a tracer, such as 11 C-methionine, which is a surrogate marker of high protein metabolism.  A high level of cell turnover in the metabolically hyperactive tumor tissue can be mapped by 18 F-fluorothymidine, which is an indicator of DNA synthesis.  In addition, many head and neck tumors contain hypoxic regions, which are radioresistant and may lead to failure of treatment. If such intratumoral regions are identified, hypoxia activated prodrugs could be administered to improve results with radiotherapy. Tirapazamine is one such agent that exhibits synergistic toxicity with radiotherapy and chemotherapy.  PET isotopes, such as 18 F-fluoromisonidazole, 18 F-FAZA, and 62 Cu-ATSM, are specific tracers of hypoxia and may be helpful in identifying hypoxic BTVs in radiotherapy planning.  However, a careful comparison of these new PET tracers with the pathologic gold standard is critical.
| » Hybrid PET-CT Scanners|| |
The utility of 18 FDG-PET for radiotherapy planning has been limited by its lack of spatial resolution and relatively low specificity. A poor spatial resolution reduces the ability of PET to locate a target to the degree of accuracy required in precision radiotherapy, such as IMRT. The advent of hybrid PET-CT scanners have allowed hardware fusion of functional and anatomic imaging, hence providing a better localization for the functional imaging. The hybrid PET-CT scanner combines PET and CT in a single large gantry and both sets of images are acquired sequentially. One of the concerns for using PET-CT for radiotherapy planning is its specificity in representing the actual dimensions of the underlying pathology. Pathologic correlation, although a gold standard, may not always be feasible. However, the target volumes defined by PET have been shown to be closest to the pathologic specimen compared with CT or MRI in laryngeal carcinoma. In this report, there was no significant difference in the volumes defined by CT and MRI, but the gross tumor volume (GTV) defined by PET was significantly smaller than CT (P = 0.02). The mean GTV delineated in the surgical specimens was smaller than the mean GTV defined by PET scan and significantly smaller than the CT scan (P = 0.003) and MRI (P = 0.001). 
| » The Impact of PET-CT on Staging of HNC and Target Volume Definition|| |
The conventional staging procedures include clinical examination, examination under anesthesia, and anatomic imaging, such as CT scan and MRI. Schwartz et al studied PET-CT scans of 20 patients who subsequently underwent neck dissection. The staging accuracy of the PET-CT was estimated to have sensitivity of 96% and specificity of 98.5% in advanced HNC. The correlation between the pathology and PET-CT was stronger than the CT scan alone.  PET-CT can play various roles in the treatment of HNC, such as upstaging the disease, differentiating a tumor from a conventionally defined abnormality, such as posttherapy changes and defining BTV for high-dose radiotherapy boost. , PET-CT may affect the management plan by detecting distant metastases, not previously identified, thus changing the intent of the treatment from radical to palliative. , Response-based therapy, where target volumes are changed as per response depicted by changes in the FDG uptake, is an interesting area of research for PET-CT.  Apart from obvious changes in the TNM staging, the detection of a larger or different primary tumor volume by PET-CT could result in the enlargement of radiotherapy volumes or, indeed, reduction in the target volume could allow dose escalation and sparing of OAR, such as salivary glands, optic chiasm, and spinal cord. A change in the number, size, and location of lymph nodes will also have an impact on radiotherapy volumes and similarly affect the dose to OAR. Target volumes defined conventionally and with PET-CT can vary significantly. Currently there is no level I evidence suggesting the use of one modality over the other. Attempts are being made to combine the benefits of multiple modalities to get more accurate representation of the tumor. Newbold et al in our institute performed a study comparing the radiotherapy volumes defined conventionally with the help of CT scan vs PET-CT and reported a significant increase in the gross tumor volume (GTV) in PET-CT group. The study suggested that there was a change in radiotherapy volume following PET-CT in patients presenting with unknown primary as well as those with known primary.  Heron et al tested PET-CT in the treatment position for radiotherapy planning in 21 patients with HNC. The primary volumes were significantly larger on the CT scan (P = 0.002), but there was no difference in the nodal volumes.  Guido et al reported results of 38 patients with HNC who were scanned with CT scan as well as PET-CT before receiving definitive radiotherapy. CT-based GTV was larger in 92% of the patients, and the difference between the CT and PET-CT volumes was statistically significant (P = 0.04).  In a similar study in 22 HNC patients, Deantonio et al reported that GTV defined with the help of PET-CT was significantly larger than the CT-based volumes (P < 0.0001) in contrast to the previous studies.  Interobserver variations in the interpretation of the scans can hamper the accuracy and standardization of the target volume definition. The variation has been reported to be more when the target definition is identified using CT alone as compared with PET-CT.  Currently there is no consensus on the role of PET-CT for target definition in the HNC and some of the main issues are discussed in the following sections.
| » Application of PET-CT for Radiotherapy Planning|| |
Conventionally, PET has been used for diagnostic investigation and these imaging protocols need to be adapted for radiotherapy planning. A diagnostic PET scan can be used for radiotherapy planning, but accurate image registration is crucial in ensuring precise target delineation. Various methods have been used to improve image registration of PET with a radiotherapy planning CT scan, such as fiducial markers, registration via transmission PET, manual registration, or automatic rigid registration. ,,, However, with the advent of PET-CT, the registration of the CT component of PET-CT with radiotherapy planning CT provides a better opportunity to improve image registration accuracy. Extra precaution must be taken while delineating target volumes in the neck where physiologic movements, such as swallowing can lead to registration error.  Ideally, a dedicated PET-CT in the treatment position in an appropriate radiotherapy immobilization device should be acquired for radiotherapy planning. It is possible to incorporate the PET or PET-CT acquired in diagnostic position into the radiotherapy planning systems with the help of newer image registration algorithms [Figure 1],[Figure 2],[Figure 3],[Figure 4].
| » Positioning of the Patient for PET-CT|| |
The couch top for diagnostic PET-CT is concave for patient comfort, while it is flat on the radiotherapy machines to enhance positional accuracy. A flat top couch accessory, which can be attached to the standard concave PET-CT couch top, should be used while using PET-CT for radiotherapy planning to ensure accurate fusion with the planning CT scan. The use of radiotherapy immobilization devices while undergoing a PET-CT will make the fusion with planning CT more accurate and reliable [Figure 5]. Patient counseling about the radiotherapy immobilization prior to the PET-CT is essential as the PET-CT takes considerably more time (approximately 40-45 min) than the standard radiotherapy planning CT (approximately 5-10 min). If the PET-CT is being performed exclusively for radiotherapy planning, the scanning time can be reduced (15-20 min) by scanning only the head and neck region on CT as well as PET, and because this requires less amount of FDG and smaller CT field, it will reduce the total radiation exposure for the patient. The presence of radiotherapy planning staff with expertise in setting up the patient in their immobilization will help to ensure consistency, accuracy, and patient comfort in the positioning.
| » Defining Edge of Target Volume on PET-CT|| |
The differences observed in target volume definition are dependent of the methods used to define the edges of the target. This is particularly challenging in PET due to the variations in which the scan data can be represented. The margins of the target lesion vary substantially depending on the method used for the assessment. The most accurate method of margin definition for the target lesions is yet to be defined and there are various methods reported in the literature.
| » Target Volume Edge Definition using PET Scan|| |
Visual assessment is used by the nuclear medicine physicians to determine the nature and margins of lesions after adjusting the window level, often with reference to the FDG uptake within the normal organs, such as the heart and liver. This method is largely operator dependent and is prone for inter-observer as well as intraobserver variations. The use of a standard contouring protocol with predefined window and color settings can help to reduce the variations in the target definition and bring the method into the realm of quantification required in radiotherapy planning.
Standardized uptake value-based methods
The standardized uptake value (SUV) is the average activity per unit volume, normalized to the injected dose of 18 FDG and patient's body weight. It is influenced by various factors, such as tissue activity factors (shape of region of interest, partial volume, and spillover effect, attenuation correction, reconstruction methods), tissue state factors (time of SUV evaluation, competing transport effects), and by normalization factors (body size, surface area, and lean body mass). ,, To define radiotherapy treatment volume or GTV, some authors have used percentage of the maximum peak SUV, while others used an arbitrary SUV value.
This method uses the fixed percent intensity level relative to the maximum activity in the tumor. Most often reported as 40-50%, but this method can lead to under- or overestimation of the tumor volume. 
This is an automated method of defining the volumes by defining a cutoff with respect to the background FDG signal. A region is contoured with intensity above a defined cutoff value. This has an advantage of being affected less by heterogeneity of the lesional tracer uptake.
Automated or semi-automated methods
These segmentation methods provide consistent target delineation with a significant saving in contouring time.  The patient data are matched with library data and the contouring is done with the help of the best-matched images from the library. These autocontouring protocols are more useful in the adaptive radiotherapy protocols where the disease is recontoured during the course of radiotherapy to adapt to the changes in target volumes. These protocols use source to background ratio to define the target volume and thus are specific to individual PET machine and cannot be generalized. Complex-shaped tumors are a challenge for these methods and the accuracy needs to be validated with pathology data. The smaller volumes tend to be slightly overestimated, whereas the larger tumor volumes could be slightly underestimated, thus introducing a systematic error.  The head and neck region presents a significant challenge for all semi-automated contouring techniques using 18 F-FDG, due to the complex patterns of normal physiologic tracer uptake.
Dose escalation to biological target volume
Interestingly, most failures of radiotherapy occur in the high dose volume suggesting that insufficient dose is being delivered, but dose escalation to the whole target volumes is limited by normal tissue toxicities. , Focusing a high-dose boost to a PET-positive volume could be an alternative approach to improve on relapse rates. In a planning study, the dose was successfully escalated from 66 to 74.9 Gy to FDG avid regions until dose-limiting criteria were reached. The elimination of the PET-negative regions from prophylactic radiation markedly reduced the dose to contralateral parotid gland (P < 0.001) and laryngeal cartilage (P = 0.001). These patients underwent surgery after the scans and none of the PET-directed IMRT plans missed pathologically verified disease.  Madani et al reported a phase I clinical trial with a 2 level dose escalation of 72.5 and 77.5 Gy to FDG-PET-defined planning target volume for 41 HNC patients. A dose-limiting toxicity of grade IV dermatitis and dysphagia was recorded at level I and the study was halted after a treatment-related death at level II dose escalation. There was no significant difference in the complete response and local control at 1 year in the 2 groups, but 1 year overall survival was significantly lower in the high-dose group (82% vs 54%, P = 0.06). In patients who relapsed, the site of recurrence was within the boost volume in 44%.  These 2 studies highlight the gap that needs to be bridged between the technologic advances making dose escalation feasible and the actual tolerance of the normal structures in HNC patients. PET using various tracers, which can delineate radioresistant, hypoxic regions, could be used to define a boost volume for dose escalation. Further clinical studies testing the feasibility of dose escalation and tolerance of normal structures are awaited.
Recently, the availability of image-guided radiotherapy has made it possible to perform a CT of the treatment region, while the patient is on the treatment machine in the treatment position. Anatomic changes in the target volumes can be mapped over the period of radiotherapy and treatment volumes can accordingly be adapted to improve the therapeutic ratio. A reduction or alteration in the target volume based on the CT scan could be further validated by PET-CT done in the treatment position. In a study of 10 patients with pharyngolaryngeal tumors, PET-based volumes were significantly smaller before radiotherapy and during radiotherapy as compared with the anatomic imaging, which resulted in the reduction in the prophylactic and therapeutic target volumes. FDG-PET-based adaptive IMRT in these patients reduced the irradiated volumes by 15-40% compared with preradiotherapy CT-based volume with a marginal impact on the doses to OAR, such as spinal cord and parotid glands.  The main reason for the limitation of using PET-CT in this setting is the difficulty in differentiation in the mucositis and target volume on the FDG-PET-CT. The availability of new tracers, which are not affected by the inflammation in the tissues, will expand the role of PET-CT in the field of adaptive radiotherapy.
Combination of CT, MRI, and PET
MRI has superior soft tissue contrast compared with CT and combining MRI with a PET-CT scan could be a good advancement in the fusion of anatomic and functional imaging. Fusion of MRI and PET has been shown to enhance the sensitivity for diagnosis of the primary lesion, lymph nodes, as well as recurrent lesions in the posttherapy setting, so this may be an avenue for advanced radiotherapy planning in the future. 
| » Conclusion|| |
FDG-PET-CT is widely accepted as a modality for evaluating HNC. PET-CT does have an impact on the radiotherapy target volumes. The role of PET-CT for radiotherapy planning is expanding and it has the potential to be employed for BTV delineation for boost-dose delivery. The development of new PET tracers will improve the specificity of response assessment during the treatment and will permit adaptive treatment methods. Major advancements in the anatomic and functional imaging technology continue to shape the radiation treatment planning process. Current literature favors multimodality imaging for radiotherapy planning and promises a better tumor definition and possibly margin reduction and dose escalation. Although the technical advancements have made it possible to use PET-CT in the radiotherapy planning process, it needs to be supported by robust clinical data in future.
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