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British Journal of Radiology (2005) Supplement_28, 18-32
© 2005 British Institute of Radiology
doi: 10.1259/bjr/72059318
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British Journal of Radiology Supplement_28 (2005),18-32 ©2005 The British Institute of Radiology

Full Paper

Experience of PET for target localisation in radiation oncology

A-L Grosu, MD1, M Piert, MD2 and M Molls, MD1

Departments of 1 Radiation Oncology and 2 Nuclear Medicine, Klinikum Rechts der Isar, Technical University Munich, Germany

Correspondence: Anca-Ligia Grosu, MD, Department of Radiation Oncology, Klinikum Rechts der Isar, Technical University Munich, Ismaninger Str. 22, Munich 81675, Germany


   Introduction
Top
 Introduction
Methods
 Results
 Discussion
 Conclusions
 References
 
For many tumour types, radiation therapy is considered an efficient method to "kill tumour cells" and the "target and destroy" principle is fundamental to its efficacy. Focusing the irradiation dose on the tumour and sparing normal tissue are the most important goals of the radiation therapy technique. This allows dose escalation for tumour tissue and dose reduction for normal tissue in order to achieve greater tumour control and a lower rate of side effects. As such, technological developments in the last decades have focused on improvements in hardware and software systems able to deliver irradiation with a high geometrical accuracy. New techniques such as stereotactic fractionated radiotherapy, radiosurgery, intensity-modulated radiotherapy (IMRT) and three-dimensional (3D) planned brachytherapy are characterised by a high level of accuracy in the delivery of irradiation to tumour tissue, sparing the surrounding normal structures and leading to a substantial improvement in treatment results. The radiation treatment plan is traditionally based on imaging data produced by CT and MRI. The enormous advantage of these investigations is the non-invasive, highly accurate anatomical 3D visualisation. Fundamental concepts in the definition of target volume were formulated based on the results of these investigations [1, 2], such as gross tumour volume (GTV), clinical target volume (CTV) and planning target volume (PTV). GTV defines the macroscopic tumour volume as defined by radiology or clinical investigation; CTV encompasses the GTV plus potential microscopic tumour infiltration; and the PTV includes the GTV and CTV plus a small margin that takes into account possible inaccuracies introduced by patient/organ motion during radiation delivery. Huge clinical experience has accumulated over the years using these investigations, but time and experience has shown not only the advantages but also the limits of CT and MRI — or of so-called "anatomical imaging". Tumour visualisation using these techniques is based on variation of tissue density (CT) or intensity (MRI), on volume effects and on contrast enhancement. However, these are not necessarily specific tumour characteristics. Similar changes may also be seen in non-tumour tissue owing to pathological conditions such as inflammation, or after therapy (surgery, radiotherapy or chemotherapy). Therefore, anatomical imaging could have limits in the presentation of tumour anatomy (tumour extension) when tumour and normal tissue have similar density (intensity) or similar properties with regard to contrast enhancement.

In recent years, new methods of tumour visualisation have advanced the domain of medical imaging. Techniques like positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance spectroscopy (MRS) enable visualisation of tumour biology, giving additional information about metabolism, physiology and molecular biology of tumour tissue. This new class of images, showing specific biological events, complements the anatomical information of traditional radiological techniques. Thus, in addition to the concepts of GTV, CTV and PTV, Ling et al [3] proposed the concepts of biological target volume (BTV) and multidimensional conformal radiotherapy (MD-CRT), which enable dose distribution to be adapted both to the morphology and the biology of the tumour. This new approach, closely related to the IMRT technique, has been named "dose painting". Thus, IMRT combined with a treatment plan based on biological imaging could be used for future biological individualisation of radiation therapy.

The first rationale for using PET in target volume delineation (TVD) is the higher sensitivity and specificity of PET for tumour tissue in comparison with CT and MRI. This has been demonstrated in many studies that compared the results of PET with the results of radiological investigations and histology. The hypothesis tested in these studies was that using PET in addition to CT and/or MRI enables GTV to be delineated with a higher accuracy. The ideal PET tracer in this situation should be taken up homogeneously by all the cells of the whole tumour and the intensity of PET uptake should be directly proportional to the density of tumour cells.

The second rationale for integrating PET in the process of radiation treatment planning (RTP) is the ability of PET to visualise biological pathways that can be targeted by radiation therapy. Imaging of hypoxia, angiogenesis, proliferation, apoptosis, etc. leads to the identification of different areas of an inhomogeneous tumour mass, areas of which can be individually targeted. For example, hypoxic areas can be treated with higher radiation doses than non-hypoxic areas. Clearly, the biological process visualised by the tracer needs to be specified. Therefore, the concept of BTV should be named after the respective tracer, e.g. BTV(FLT-PET), BTV(FAZA-PET) [4].

The goal of this paper is to summarise data of the current literature regarding the use of PET for TVD in the process of RTP. Biochemical and clinical background, consequences for GTV, CTV and PTV delineation, and future perspectives and problems are discussed. We focus especially on TVD (excluding the role of PET in tumour staging and treatment monitoring), as we consider this topic extremely important. PET/CT technology is entering into the clinic and is increasingly being used by radiation oncologists in the decision-making process. In addition, some relevant research projects undertaken by our research group at Munich Technical University are introduced and certain pertinent findings are presented.


   Methods
Top
 Introduction
 Methods
Results
 Discussion
 Conclusions
 References
 
Data were collected by performing a Medline search using the following keywords: PET, biological imaging, target volume, radiation treatment planning (RTP); and the following cancer types: lung cancer, head and neck cancer, gastro-oesophageal and colorectal cancer, anal cancer, gynaecological cancer (ovarian, cervical and uterine cancer), breast cancer, prostate cancer, lymphoma (Hodgkin's and non-Hodgkin's), melanoma, sarcoma and brain tumours. Only tumours in which the value of PET for TVD (GTV, CTV or PTV) was studied for RTP are included. For some tumour types we found no data in the literature, so they were excluded from this review, even if the sensitivity and specificity in diagnosis/staging was demonstrated to be very high (e.g. breast cancer, melanoma). Prostate cancer was specifically included, considering the interesting experience of our department with the integration of choline-PET in RTP and the high impact of this tumour in radiation oncology.

In the first part we discuss the role of PET in tumour tissue detection. For each PET tracer presented, we briefly discuss its biochemical and metabolic background. The rationale for using a tracer in TVD is the large clinical experience with a particular tracer in primary diagnosis, staging and diagnosis of tumour recurrence. The results of clinical trials including fluorodeoxyglucose (FDG)-PET in cancer diagnosis were summarised by Gambhir et al [5]. This was a subset of the original document submitted to the Health Care Financing Administration (HCFA) to request expanded Medicare reimbursement for FDG-PET in the USA. Considering that this document exhaustively analysed the impact of FDG-PET on treatment strategy and diagnosis, we used these data as rationale for integrating FDG-PET into RTP. We summarise the trials analysing the impact of PET on GTV, CTV or PTV delineation. The number of investigated patients and the percentage of cases in which PET influenced the TVD (increasing or decreasing the outlined volume) are quantified for each tumour type.

In the second part we analyse the role of PET in the visualisation of biological pathways, an approach that could become the support for a biological-based radiation treatment (dose painting). Hypoxia, tumour proliferation and tumour angiogenesis will be discussed as potential biological targets for MD-CRT.


   Results
Top
 Introduction
 Methods
 Results
Discussion
 Conclusions
 References
 
PET for tumour detection and delineation of the gross tumour volume (GTV)
FDG-PET
Malignant tumour cells are characterised by increased glycolysis. Whole-body imaging using PET and the fluorine-18-labelled glucose analogue fluorodeoxyglucose (18F-FDG) is based on this observation [6]. The high sensitivity of FDG-PET imaging is related to the upregulation of glucose transport into cells as well as the increased hexokinase reaction in most malignancies. Following phosphorylation by hexokinase, FDG becomes trapped in cells, leading to an uptake into tissue in proportion to the overall glucose metabolism. Since glucose metabolism is also generally increased in inflammatory processes, FDG uptake is not tumour specific. The enhanced FDG uptake in inflammatory diseases could therefore limit the use of FDG-PET in RTP. However, the rationale for the integration of FDG-PET in RTP is the higher sensitivity and specificity of FDG-PET for tumour tissue in comparison with CT alone. FDG is the most widespread PET tracer used in oncology.

FDG-PET for GTV delineation in lung cancer
Traditionally, TVD in lung cancer is based on CT. In a tabulated summary of the FDG-PET literature, Gambhir et al [5] evaluated 53 clinical trials (total of 4005 patients) that analysed the role of FDG-PET in lung cancer staging. In these studies, the average FDG-PET sensitivity and specificity were 83% and 91%, respectively, whereas for CT they were 64% and 74%, respectively. In 1565 patients studied, change in patient management following FDG-PET staging data was estimated at 37%.

The role of FDG-PET in the GTV and PTV delineation for RTP of lung cancer has been investigated thoroughly in a total of 455 patients evaluated in 13 trials [7–19]. These are summarised in Table 1Go. In these investigations, GTV, CTV and PTV delineated using CT alone were compared with target delineation using additional FDG-PET. CT/PET image fusion methods were used in only six trials. Two studies used the integrated PET/CT system. All of the studies indicated that FDG-PET adds essential information to CT results with significant consequences on GTV, CTV and PTV delineation. The percentage of cases presenting significant changes in tumour volume after the integration of FDG-PET investigation results in the RTP ranged from 21% to 100%. Twelve studies pointed out the significant implications of FDG-PET in staging lymph node involvement. In addition, the improved delineation of malignant tissue from atelectasis using FDG-PET compared with CT has been demonstrated. CT-based RTP may overestimate or underestimate the extension of GTV because of the inability of CT to make the distinction between benign or malignant tissue. Therefore, using FDG-PET, the target volume can be enlarged, incorporating additional tumour tissue, or can be reduced leading to a reduction of the irradiated normal tissue and thus permit an escalation of the irradiation dose. A further important result of some of the studies was the fact that the interobserver variability of GTV and PTV definition may be significantly reduced [19].


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  		Table 1. FDG-PET for target volume delineation in lung cancer

 
In a recent study, van der Wel et al [18] estimated an increase in tumour control probability (TCP) in lung cancer from 13% to 18% if FDG-PET was incorporated into RTP compared with CT-based radiotherapy alone. Ling et al [20] used a mathematical model to test the hypothesis that improvements in local control following radiation therapy in patients with non-small cell lung cancer could be made by the following methods: improved target definition with the combined use of PET/CT; improved tumour coverage by reducing uncertainties from set-up and respiration motion; and dose escalation. The authors pointed out the importance of the consideration of all these factors in clinical trials, because studies of a single factor without addressing the others may lead to false results and conclusions.

In conclusion, as GTV delineation is a fundamental step in RTP, the use of combined CT/PET imaging for all dose escalation studies with either conformal radiotherapy or IMRT has been recommended by the Radiation Therapy Oncology Group (RTOG) as a standard method in lung cancer [21].

FDG-PET for GTV delineation in head and neck cancer
In several studies, the sensitivity and specificity of FDG-PET for the detection of lymph node metastases, unknown primary tumour or tumour recurrence after previous treatment was higher compared with MRI and CT. Summarising the data of eight studies (468 patients) that evaluated the impact of FDG-PET in staging of head and neck cancer, the average sensitivity and specificity for FDG-PET were 87% and 89%, respectively, whereas for CT these figures were 62% and 73%, respectively [5]. The sensitivity and specificity of FDG-PET for head and neck cancer diagnosis, assessed in seven trials incorporating 193 patient studies, were 93% and 70%, compared with 66% and 56%, respectively, for CT. However, several studies report false-negative FDG-PET results observed in micrometastatic disease. False-positive FDG-PET findings are described in inflammatory lymph nodes and in some structures such as tonsils and salivary glands where FDG uptake may be increased. Therefore, the conclusion of many studies is that this technique cannot entirely replace histological tissue diagnosis.

The impact of FDG-PET for TVD in head and neck cancer was investigated in five trials [16, 22–25] incorporating 136 patients with different tumour stages and locations (Table 2Go). These studies showed that FDG-PET could have a significant impact on GTV delineation in comparison with CT (or MRI) alone in 9–100% of cases. In 5–58% of patients, FDG-PET lead to an increase in GTV, whereas in 33–75% of the cases GTV was reduced using PET. FDG-PET seems to help to focus the dose on the gross tumour mass, enabling sparing of normal tissue, especially of the parotid gland.


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  		Table 2. FDG-PET for target volume delineation in head and neck cancer

 
However, only two studies [23, 25] used MRI/CT/PET image fusion for GTV delineation. In all other trials, FDG-PET was generally compared with CT alone, in many cases performed without contrast medium application. The sensitivity and specificity of CT for head and neck cancer are lower than those of MRI [26]. Therefore, comparative studies of MRI/CT vs FDG-PET based on image fusion and correlated with the histological results are required for a more accurate evaluation of the impact of FDG-PET in TVD of head and neck tumours.

The most systematic evaluation of tumour extension on FDG-PET, CT and MRI was carried out by Daisne et al [25], who also compared the results of these investigations with surgically removed tissue. The evaluation is based on a robust study design, image co-registration and automatic GTV delineation on PET. Validation of this method has been described in detail in previous studies [27, 28]. GTVs outlined on CT and MRI were relatively similar, whereas GTVs delineated on FDG-PET and surgical specimens were significantly smaller. FDG-PET was the most accurate investigation modality; discrepancies between CT/MRI and surgical specimens were significant. However, no imaging modality managed to depict superficial tumour extension. On the other hand, GTV was outlined outside of the tumour areas on surgical specimen in all three investigations. The authors summarised that FDG-PET was found to be the most accurate investigation modality, but considering the complex design of the study, the low number of evaluated patients and the possible important consequences on the radiation treatment, they avoid drawing a definitive conclusion, mentioning that further evaluations are required. We consider that the robust design of this study could be also used for other tumour entities.

Experimental data suggest that methionine (MET), an amino acid tracer, has a high sensitivity and specificity for squamous cell carcinoma [29]. Based on this observation, FDG-PET for tumour mass delineation in head and neck cancer was compared with MET-PET and CT. Evaluation of 23 patients suggested no advantage using MET-PET. One reason for this was the high uptake in salivary glands, which led to false-positive results [30].

In conclusion, the role of PET in RTP of head and neck cancer is still under investigation. If these initial results showing that FDG-PET could have an essential impact on GTV delineation can be confirmed by further evaluations, they would have a significant impact on RTP.

FDG-PET for GTV delineation of gastrointestinal tract (GIT) cancer
Generally, FDG-PET has had a significant impact in diagnosis and staging of GIT cancer. For lesions located in the gastro-oesophageal tract, the average sensitivity and specificity of FDG-PET for diagnosis of primary tumour, evaluated in five trials that included 168 patient studies and 545 lesions, were 80% and 95%, respectively, whereas these figures for CT were 68% and 81%, respectively. In one study based on 99 patients with 276 lesion sites, which evaluated FDG-PET for tumour diagnosis, staging and follow-up, patient management was changed in an estimated 14% of cases [5]. Assessment of the role of FDG-PET in colorectal cancer focused on tumour recurrence after primary treatment, re-staging and assessing response to treatment. In 2244 evaluated cases, the average sensitivity and specificity of FDG-PET to detect tumour recurrence were 94% and 87%, respectively, compared with 71% and 89%, respectively, for CT. For staging, the estimated change to patient management was 36% as evaluated on 236 patient studies [5]. However, GIT studies that compare tumour extension by FDG-PET, CT, endoluminal ultrasound (EUS) and MRI with the histological result are rare.

There are only a small number of trials in the literature that have analysed the value of FDG-PET in GTV delineation for RTP of GIT tumours. Vrieze et al [31] determined the additional value of FDG-PET to optimise CTV delineation in patients with advanced oesophageal carcinoma. They found discordances in 14/30 (47%) patients in detection of pathological lymph nodes between CT/EUS and FDG-PET. The authors take into consideration the possibility of false-negative results in FDG-PET and indicate not to reduce the PTV based on a negative FDG-PET result, but owing to the high specificity of FDG-PET, they indicate to include PET-positive lymph nodes in the irradiation field, even when the EUS/CT is negative.

Ciernik et al [16] investigated the impact of integrated PET/CT in GTV delineation of six patients with rectal cancer and seven with anal cancer. In rectal tumours, GTV increases of more than 25% of the CT volume were observed in 3/6 (50%) patients, and decreases were seen in 1 patient (17%). In anal cancer, FDG-PET resulted in an increase of GTV of more than 25% in 3/7 (43%) patients, and decreases resulted in 1 case (14%). In a recent publication [32], the same group proposed an automated biological image-guided RTP for rectal cancer based on FDG-PET. The BTV defined for appropriate GTV assessment was set at a single peak threshold of 40% of the signal of interest.

In conclusion, the majority of nuclear medicine studies reported an increased accuracy of FDG-PET for tumour diagnosis, staging or recurrence in comparison with CT. Further histological-based studies analysing the precision of the investigation with regard to local tumour extension as well as comparisons with EUS and MRI are necessary to define exactly the real impact of FDG-PET for GTV delineation in GIT cancer.

FDG-PET for GTV delineation in gynaecological cancer
The sensitivity and specificity of FDG-PET for primary diagnosis of an ovarian/pelvic mass, uterine cancer and cervical cancer evaluated in 284 patients in six studies were 66% and 77%, respectively, compared with 100% and 67%, respectively, for CT. For staging, the evaluation encompassed four trials incorporating 399 patients. The FDG-PET sensitivity and specificity were 54% and 96%, respectively, compared with 48% and 76%, respectively, for CT. Considering tumour diagnosis and staging together (three trials, 126 patients), the sensitivity and specificity of FDG-PET were 86% and 82%, respectively, and for CT they were 79% and 59%, respectively. The impact of FDG-PET in diagnosis of recurrence was evaluated in 11 trials that included 417 patients. The sensitivity and specificity of FDG-PET were 88% and 90%, respectively, whereas the figures for CT were 76% and 75%, respectively. For the detection of tumour recurrence, a change to patient management was estimated to occur in 17% of cases when FDG-PET investigations were considered [5].

In a recent study, Lamoreaux et al [33] compared the results of CT and FDG-PET in the diagnosis of primary tumour and lymph node metastases in 23 patients with carcinoma of the vagina. They found abnormal uptake in the region of the primary tumour in all 21 investigated patients with intact tumour, whereas CT visualised it in only 43% of cases (9/21 patients). Pathologically involved lymph nodes were identified in 4/23 (17%) patients on CT and in 8/23 (35%) cases on PET. Despite the fact that the data were not verified histologically, these results are comparable with the data reported in cervix cancer, supporting the idea that FDG-PET is able to detect tumour tissue in gynaecological cancer and will play an important role in future RTP.

However, the clinical experience with FDG-PET in TVD in gynaecological cancer is still limited. FDG-PET was integrated in the RTP of four patients with cervical cancer [34]. The standard radiation treatment in these patients includes the pelvic region, but para-aortic nodes are not routinely integrated into the PTV. In these four cases, in addition to CT, FDG-PET positively identified para-aortic lymph node involvement. Therefore, this region was defined as the gross disease and was included in the PTV and irradiated with a higher dose. The other regions, representing the CTV, were treated with a lower dose in the same irradiation session. This different dose distribution in a PET-guided defined "target within target" was realised using IMRT. Although this study was performed on a small number of patients, the validity of a biologically-guided IMRT was demonstrated.

Using an integrated PET/CT, Ciernik et al [16] evaluated eight patients with cervix cancer and compared CT alone with FDG-PET/CT. A smaller and a larger GTV were seen in two of eight patients, and the changes in PTV were approximately 20%.

FDG-PET has also been used for tumour visualisation in brachytherapy treatment planning [35]. The first FDG-PET for tumour volume definition was followed by a second PET, where the FDG tracer was placed inside the tandem and ovoid applicators to visualise the treatment source positions for 3D treatment planning. The authors show that this technique has potential to improve tumour coverage in patients with cervical cancer and to spare organs at risk.

To summarise, preliminary data have shown that FDG-PET could be helpful to identify pathological lymph nodes with a higher specificity than CT, and FDG-PET may help to contour the gross tumour mass. However, further studies are required to prove these hypotheses.

FDG-PET for GTV delineation in lymphomas
The impact of FDG-PET for Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) has been investigated in a large number of trials that analysed the impact of FDG-PET on staging, diagnosis and detection of recurrence. The sensitivity and specificity of FDG-PET for tumour tissue evaluated in staging studies that incorporated 1796 patients were 90% and 93%, respectively, in comparison with 81% and 69%, respectively, for CT [5].

Although there are a large number of studies documenting the high impact of FDG-PET in the treatment strategy of HD and NHL, there are only preliminary data systematically analysing the impact of FDG-PET in TVD for RTP. Using an example case of paediatric HD, Krasin et al [36] discuss the role of PET and its incorporation into radiation treatment in paediatric radiation oncology. In a review of the literature of FDG-PET in the clinical management of HD, Hutchings et al [37] comment that the role of PET in selection of patients for radiation therapy is very unclear and PET could be particularly relevant in difficult anatomical regions where it is essential to spare normal tissue. Lavely et al [38] showed that a negative PET scan after completion of therapy does not exclude the presence of residual microscopic disease in HD and NHL. In patients with negative FDG-PET after completion of first-line treatment, the rate of local recurrence was higher in the subgroup treated with chemotherapy alone in comparison with combined modality therapy (chemotherapy plus radiation therapy). The authors concluded that radiation treatment volumes might be better planned from the initial staging PET study. The first evaluation of the differences in CT- and FDG-PET-based GTV delineation was carried out in ten patients with thoracic lymphomas [39]. In six of ten patients, the GTV defined by PET was smaller than the GTV defined by CT; in two cases the difference was greater than 12 cm. The authors concluded that FDG-PET could reduce the subjectivity in target delineation of thoracic lymphomas.

In conclusion, considering the significant impact of FDG-PET in the treatment of HD and NHL, further systematically designed trials, which include histological evaluation and prospective clinical follow-up, are required to assess the real impact of PET on TVD.

Choline-PET
Phosphatidylcholine, a phosphorylated form of choline, is an essential component of the cell membrane [40]. The amount of choline uptake in tumour cells is generally dependent on two main metabolic steps: the (non-specific) transport from the blood to the tumour cell; and the specific phosphorylation of choline catalysed by the enzyme choline kinase, which is upregulated in cells with a higher rate of proliferation. However, it has not been possible to demonstrate that in vivo uptake of 11C-choline correlates with cell proliferation [41]. Intracellular choline appears to be involved in cell signal transduction and apoptosis, but these mechanisms are not completely understood. The alteration in the choline/citrate ratio in malignant tumours has been demonstrated in vivo by MRS [42, 43].

Choline-PET for GTV delineation in prostate cancer
The promising results with MRS in treatment planning and monitoring of prostate cancer, and the low impact of conventional radiological investigations in the diagnosis of this cancer, raises the question whether choline-PET could deliver more information about tumour location, metastases and recurrence. Sixty-seven pre-operative patients with prostate cancer were prospectively investigated with 11C-choline-PET, MRI and CT. For the diagnosis of lymph node metastases of prostate cancer by 11C-choline-PET, a sensitivity of 80%, a specificity of 96% and an accuracy of 93% have been reported [44].

We have initiated a study to investigate the value of 11C-choline-PET in TVD for IMRT in prostate cancer. The goal of our study is to evaluate whether 11C-choline-PET can be used to delineate the gross tumour mass in the prostate, which could then be irradiated with a higher dose using IMRT. Some preliminary results are shown in Figures 1 and 2GoGo. Systematic comparisons of the PET results with tumour pathology investigations after prostatectomy are necessary to establish the validity of this approach. The importance of 11C-choline-PET in the diagnosis of recurrence after surgery is also under investigation. The results of this study could have a significant impact on TVD for prostate cancer.



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  		Figure 1. Patient with prostate cancer investigated using an integrated PET/CT. Upper-left: choline-PET/CT image fusion based on three-dimensional (3D) coordinates. Upper-right: choline-PET. The pathological choline uptake could help to visualise the gross tumour mass in the prostate. Below: CT before PET and CT after PET, co-registered using 3D coordinates, documenting the patient's movements during the investigations, which raise concerns about the accuracy of the PET/CT image fusion using integrated PET/CT and data co-registration based on 3D coordinates.

 


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  		Figure 2. Choline-PET/CT in prostate cancer ((a) choline-PET; (b) three-dimensional-based image fusion after integrated PET/CT). Intensity-modulated radiotherapy and dose painting based on choline-PET. The area with intensive choline-PET (pink) corresponds to gross tumour mass, which may benefit from irradiation with 2.4 Gy/fraction. The remaining prostate (green) could receive 2 Gy/fraction. However, the validity of this hypothesis has to be evaluated in further pathological and PET investigations. The PET studies were performed in co-operation with the Department of Nuclear Medicine, Technical University Munich, Director Prof. M Schwaiger.

 
Amino-acids PET
11C-labelled MET, 123I-labelled alpha-methyl-tyrosine (IMT) and 18F-labelled O-(2-18F-fluoroethyl)-L-tyrosine (FET) are the most important radiolabelled amino acids used in the diagnosis of gliomas. Tumour cells take up radiolabelled amino acids at a high rate, whilst only a low uptake occurs in normal cerebral tissues. The uptake in tumour cells is mediated by specific amino acid transporters. At the level of the blood–brain barrier (BBB) they are independent from the BBB disturbance [45, 46].

MET-PET for GTV delineation in brain gliomas
In brain gliomas, the sensitivity and particularly the specificity of MET-PET for tumour tissue are higher compared with CT and MRI. Evaluating MET-PET, MRI, CT and stereotactic biopsy results, Bergstrom et al [47], Mosskin et al [48], Ogawa et al [49] and Braun et al [50] suggested that MET-PET has a higher accuracy in defining the extent of gliomas than either CT or MRI. Herholz et al [51] showed sensitivity and specificity of MET-PET in differentiating between non-tumour tissue and low-grade gliomas of 76% and 87%, respectively. However, MET uptake appears to be higher in high-grade gliomas compared with low-grade gliomas, but a high MET enhancement was observed in low-grade oligodendrogliomas. In conclusion, MET is a very efficient tracer for tumour tissue identification, especially in high-grade gliomas.

Although PET offers superior spatial resolution (3–4 mm) compared with SPECT (7–8 mm), MET-PET and IMT-SPECT are comparable in their ability to identify tumour tissue [52].

To date, only limited data are available in the literature regarding the value of amino acid tracers in RTP of gliomas. Voges et al [53] reported MET-PET as a diagnostic tool for cerebral gliomas and as a monitoring tool for brachytherapy with 125I seeds. Forty-six patients with suspected brain tumours were investigated with MET-PET. In 67% of cases, the spatial extent of increased tracer uptake in gliomas was larger than that of the contrast enhancement on CT/MRI images, whilst in the remaining 33% of cases the extent of tumour tissue was diagnosed with comparable accuracy. One year after seed implantation, a significant decline of MET uptake was noticed. The authors concluded that MET-PET might improve the definition of brain tumour extension and provide valuable information regarding therapeutic effects. Julow et al [54] introduced MET-PET in RTP for interstitial irradiation of brain tumours with stereotactically-implanted 125I seeds. They showed that CT/MRI/PET or SPECT image fusion helped to improve accuracy and minimised the perifocal morbidity of interstitial irradiation. Nuutinen et al [55] reported the feasibility of MET-PET for RTP and monitoring patients with low-grade gliomas. In comparison with MRI, MET-PET was helpful in outlining the GTV in 3/11 (27%) cases, whereas it was complementary to MRI in 46% of cases and less distinctive in 27%.

We analysed the impact of MET-PET in GTV delineation for RTP of 39 patients with operated gliomas (see Figure 3Go) [56]. In 7/39 (18%) patients, MET uptake corresponded exactly to gadolinium (Gd) enhancement, whereas in 31/39 (79%) cases the region of MET uptake was larger than that of the Gd enhancement. In 29/39 (74%) patients the Gd enhancement area extended beyond the MET enhancement. MET uptake was detected up to 45 mm beyond Gd enhancement. MET-PET vs T2 MRI was investigated in 18 patients. MET uptake did not correspond exactly to hyperintense areas on T2 MRI in any patient: in 9/18 (50%) cases, the uptake of MET was extended beyond the hyperintensity on T2 images, whilst in 18/18 (100%) patients at least some hyperintensity on T2 MRI was located outside the MET enhancement area. MET uptake was detected up to 40 mm beyond the hyperintensity area on T2 MRI. Similar results were also reported with IMT-SPECT [57, 58] and proton MRS [59–61].



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  		Figure 3. (Left to right): methionine (MET)-PET, CT with contrast and T1 MRI with gadolinium (Gd) were co-registered and integrated in the radiation treatment planning of a patient with astrocytoma (WHO stage III), 2 weeks after surgery. The residual tumour (shown by the area of increased MET uptake on the PET scan) is delineated in pink. This region was delineated as the gross tumour volume and was treated with a higher dose (the isodose distribution for the boost volume is shown in green). The yellow arrows show a region of contrast enhancement without MET uptake on PET — this was considered to be due to disturbance of the blood–brain barrier (BBB) as a consequence of surgery and was excluded from the high-dose irradiation area. In this case, MET-PET helped to differentiate between the areas of contrast enhancement due to BBB disturbance after surgery and those due to residual tumour. The PET studies were performed in co-operation with the Department of Nuclear Medicine, Technical University Munich, Director Prof. Dr M Schwaiger, Germany.

 
A recent analysis of an IMT-SPECT-planned or MET-PET-planned group of patients with recurrent gliomas re-irradiated using stereotactic fractionated radiotherapy (6 x 5 Gy) and temozolomide suggested that integration of amino acid-PET or SPECT in TVD might contribute to an improved outcome [62]. This is the first study showing an advantage in patient survival using additional biological imaging for TVD in comparison with anatomical imaging alone.

FET-PET for GTV delineation in brain gliomas
The short physical half-time (~20 min) of 11C-MET limits its clinical usefulness to centres with onsite cyclotrons. The advantage of the amino acid analogue FET is that it can be radiolabelled with fluorine-18, an isotope with a physical half-life of ~110 min, allowing it to be distributed to PET centres without an onsite cyclotron. In several studies, both in animal models and in patients, MET-PET and FET-PET have been demonstrated to be equal in their ability to diagnose vital tumour tissue [63, 64].

FDG-PET for GTV delineation in brain gliomas
Accumulation of FDG in the brain is closely related to glucose metabolism. Unlike other tissues, the brain utilises glucose almost exclusively to meet its energy demands. Consequently, the accumulation of FDG in normal brain tissue, especially in the grey matter, is very high. Therefore, brain tumours with increased FDG uptake may be indistinguishable from normal brain tissue, limiting the usefulness of FDG for brain tumour imaging. The value of FDG-PET in 3D treatment planning was systematically analysed by Gross et al [65]. In 18 patients with malignant brain gliomas, the tumour volume defined by PET was compared with the tumour volume defined by PET/MRI fusion images. Additional information from FDG-PET for RTP was minimal owing to the low contrast between viable tumour and normal brain tissue.

MET-PET for GTV delineation in meningiomas
Meningiomas show a high MET uptake on PET. In meningioma, the GTV is routinely delineated by considering the contrast enhancement areas on CT and MRI and bone windowing on CT. Meningiomas usually infiltrate the region of the sella, cavernous sinus, orbit, tentorium, falx cerebri and dura mater structures. Difficulties in defining the tumour extension may occur because contrast enhancement in these regions in normal tissue may be comparable with that of the tumour itself. We investigated the role of MET-PET in TVD for stereotactic fractionated radiotherapy in nine patients with meningiomas. MET-PET data were co-registered with the CT and MRI data using software based on mutual information. We observed that by using MET-PET/CT/MRI fused images, meningioma borders can be more accurately defined with respect to critical normal organs, especially in critical regions of the base of the skull, where, in some cases, the normal contrast enhancement of the dura cannot be differentiated from meningioma infiltration [66].

PET for delineation of the biological target volume (BTV) and "dose painting"
Using biological imaging, a biological pathway with special significance for tumour response to the treatment could become the target of radiation therapy. Examples of this are hypoxia-specific, tumour cell proliferation-specific, or tumour angiogenesis-specific PET.

Hypoxia PET
Many in vitro and in vivo studies have shown that tumour hypoxia is associated with an increased resistance to radiation and chemotherapy, as well as local recurrence and distant metastasis [67–72]. PET seems to be a very promising approach for visualising hypoxia in vivo. Hypoxia tracers should fulfil several essential conditions: (1) to be captured specifically by hypoxic cells using an oxygen-specific retention mechanism; (2) to be sufficiently delivered in a perfusion-limited microenvironment; (3) to produce a low level of non-specific metabolites; and (4) labelled metabolites of hypoxia tracers should not be found in the circulation at the time of imaging. None of the present hypoxia tracers available completely meet all these requirements [4, 73].

Several bioreductive substances have been evaluated as hypoxia tracers, mainly nitroimidazole compounds, e.g. 123I-iodoazomycin arabinoside (123I-IAZA), 18F-fluoromisonidazole (18F-FMISO) and 18F-azomycin arabinoside (18F-FAZA), where the bioreductive molecule accepts a single electron leading to free radical metabolites that are further reduced and bound to cell constituents under hypoxic conditions. 18F-FMISO was the first nitroimidazole compound developed for PET [74–76].

Besides nitroimidazole compounds, metal complexes such as 99Tcm-labelled dioximes (99Tcm-HL91) and 60Cu-labelled methylthiosemicarbazone (60Cu-ATSM), being bioreductive molecules themselves, have been proposed for tumour hypoxia imaging. In a clinical pilot study, Chao et al [77] demonstrated the feasibility of 60Cu-ATSM-PET-guided radiotherapy planning in head and neck cancer patients. Nevertheless, the tumour-to-background ratio in hypoxic tumour tissues did not dramatically differ from earlier studies using 18F-FMISO and other nitroimidazole compounds. The authors reported the integration of hypoxia tracer Cu-ATSM in RTP of patients with locally advanced head and neck cancer treated with IMRT. They developed a CT/PET fusion system based on external markers, and the GTV outline was based on radiological and PET findings. Within the GTV, regions with a Cu-ATSM uptake twice that of contralateral normal neck muscle were operationally selected and outlined as hGTV. The IMRT plan delivered 80 Gy in 35 fractions to the ATSM-avid tumour subvolume (hGTV), and the GTV received simultaneously 70 Gy in 35 fractions, keeping the radiation dose to the parotid glands below 30 Gy. Rischin et al [78] used [18F]-FMISO scans to detect hypoxia in patients with T3/4, N2/3 head and neck tumours treated with tirapazamine, cisplatin and radiation therapy. Fourteen of 15 patients were hypoxia-positive at the beginning of the treatment, but only one patient had detectable hypoxia at the end of radiochemotherapy.

We are in the process of analysing the feasibility of 18F-FAZA-PET for the visualisation of tumour hypoxia and subsequent biologically-adapted RTP in patients with head and neck tumours. An example of FAZA-PET/CT-based dose painting using IMRT in head and neck tumours is shown in Figure 4Go.



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  		Figure 4. Integrated 18F-azomycin arabinoside (FAZA)-PET/CT in a patient with larynx squamous cell carcinoma. The PET/CT image fusion ((a) axial; (b) coronal; (c) intensity-modulated radiotherapy dose painting). The hypoxic area (biological target volume) is treated with 2.4 Gy/fraction; the gross tumour volume, based on radiological and clinical data is treated with 2 Gy/fraction. However, the validity of this hypothesis has to be evaluated in future trials. The FAZA-PET/CT studies were performed in co-operation with the Section of Radiopharmacy, University Tübingen, Prof. Dr H J Machulla, and the Department of Nuclear Medicine, Technical University Munich, Prof. Dr M Schwaiger, Germany. *In this picture the left and right side are changed.

 
FLT-PET
Fluorine-18-labelled thymidine analogue 3'-deoxy-3'-[18F]fluorothymidine (FLT) accumulation in tumour cells has been shown to correlate with tumour cell proliferation as assessed by the Ki-67 labelling index. This tracer is retained in proliferating tissues primarily through the enzyme thymidine kinase [79–81]. There are no data in the literature regarding the integration of FLT-PET in RTP. However, if clinical and experimental studies confirm the hypothesis that this tracer has a high sensitivity and specificity for proliferating tissue, this investigation could play an important role in the development of new image-based dose distribution and treatment fractionation strategies.

RGD-PET
The {alpha}v{beta}3 integrins are important receptors for cell adhesion involved in tumour angiogenesis and metastasis. They mediate migration of activated endothelial cells through the basement membrane during formation of new blood vessels. It is of particular interest that these integrins are expressed only on the cell surface of activated endothelial cells, but not on normal endothelial cells of established vessels. Haubner et al [82] described the non-invasive imaging of {alpha}v{beta}3 integrin expression using 18F-labelled RDG-containing glycopeptide and PET. First imaging results using small animal PET studies suggest that this compound is suitable for the non-invasive determination of {alpha}v{beta}3 integrin expression. Recently, Beer et al showed that 18F-galacto-RGD-PET enables non-invasive quantitative assessment of the {alpha}v{beta}3 expression pattern on tumour and endothelial cells in patients with malignant tumours [83]. This raises the question whether this information can be used as a target for new radiotherapy and systemic treatment regimens.


   Discussion
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 Methods
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 Discussion
Conclusions
 References
 
This paper summarises the data of the current literature regarding the use of PET in TVD for RTP. The results of the presented trials show that, using different tracers, PET has a high potential to give additional information to CT and MRI regarding tumour morphology and biology, and this information could have a significant impact on RTP. Tracers with a high sensitivity and specificity for tumour tissue, such as FDG, MET, FET or choline, can bring additional information to CT and MRI and can be used to define the tumour location with a higher accuracy. Taking the co-registration of biological imaging with anatomical imaging as a base for TVD, the treatment can be focused with a higher precision. Tracers that visualise biological pathways implicated in tumour response to radiotherapy, such as FMISO or FAZA for tumour hypoxia, FLT for tumour proliferation, or RGD for tumour angiogenesis, can be used to target biologically-active subvolumes of the tumour using IMRT-based dose painting. Both approaches help to spare surrounding normal tissue, enabling escalation of the irradiation dose. However, some criticisms remain.

The integration of PET in gross TVD for RTP is based on the observation, supported in many nuclear medicine studies, that the sensitivity and specificity of PET for tumour tissue is, for many tumour entities, higher in comparison with the traditional radiological investigations of CT and MRI. However, in general, these studies evaluate the presence or absence of pathological uptake, and not the extension (morphology) of the PET result in comparison with the radiological and pathological result. Considering the heterogeneity of tumour tissue, it could be possible that in some cases PET identifies only a part of the tumour mass that is sensitive to the PET tracer. Therefore, the sensitivity and specificity of PET for the presence or absence of tumour tissue is not equivalent to the capacity of PET to show the extension of tumour tissue, which has to be demonstrated by comparing the tumour extension on PET with results of tumour biopsy or evaluation of surgical specimens. There are only a few examples using this approach, such as the studies of Daisne et al [25] of FDG-PET in head and neck cancer, Mosskin et al [48] of MET-PET in brain gliomas, or the evaluation of MRS for tumour delineation in prostate cancer [42, 43]. These studies are extremely important because they help us to understand the accuracy of PET imaging from a radio-oncological point of view, which is sometimes different from the point of view of the radiologist or oncologist.

The technique of gross tumour mass delineation using PET is different from study to study. Many trials use visual interpretation of PET, and tumour contours are outlined manually by the physician. In other studies automatic methods are used, which are based on a threshold value, defined using different algorithms: standard uptake value (SUV) higher than 2.5 for tumour tissue, minimal SUV in tumour 40% or 50% from maximal tumour SUV, tumour/background index etc. Nestle et al [84] compare and discuss critically all these approaches, showing that the differences in tumour extension using different algorithms for volume delineation could lead to significant differences between the quantified volumes. Therefore, each institution has to define exactly the method used for tumour outlining. However, delineation methods that use the tumour-to-background algorithm appear to have a higher accuracy. The lower resolution of PET images ( ~3 mm for head and 5–6 mm for the body) has to be taken in consideration. In some special cases, PET/CT/MRI image fusion is useful because the biological information of PET can be combined with the high accuracy of the radiological investigations in the delineation of gross tumour mass.

Co-registration of PET data with the CT or MRI data is an important step in RTP. The accuracy of image fusion has essential consequences in radiation oncology, more than in other medical domains: it has an impact on target delineation and on the spatial delivery of irradiation, which is generally based on CT. The methodology of image fusion should be adapted to different tumour locations and PET tracers. Therefore, special image fusion protocols must be developed and validated for each new tracer and each tumour location. Integrated PET/CT scanners are a valuable tool to improve imaging for RTP, but are not the final solution for the image registration problem. Patient and tumour motion artefacts due to movements between the two investigations, ventilation, pulsation etc., specifically need to be addressed. For tumours located in the chest and abdomen it can be expected that respiratory gating during PET/CT and radiation treatment can overcome this specific problem in the future. Figure 2Go shows an example from our institution of choline-PET for RTP in prostate cancer. CT before PET and CT after PET, co-registered using 3D coordinates, document the patient's movements during the investigations, which raise questions about the accuracy of the PET/CT image fusion using integrated PET/CT and data co-registration based on 3D coordinates.

Based on a biological paradigm, PET-visualised biological pathways give information about metabolism, physiology and molecular biology of tumour tissue. It is a fascinating idea to use this information as a target for radiation therapy, to mould the radiation fields and the dose to the biological information provided by PET in addition to the anatomical information of CT and MRI. However, this is only a hypothesis that has to be validated in experimental and clinical studies. There are many questions to be answered and problems to be solved: which is the most useful biological property to target — tumour hypoxia, proliferation or angiogenesis? What is the dynamic of these biological events under radiation therapy? What should be the optimal radiation treatment schedule? What is the impact of these investigations on the combination of radiotherapy with other treatment modalities? The only method to reduce the high level of entropy is to bring more information into the system.


   Conclusions
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 Introduction
 Methods
 Results
 Discussion
 Conclusions
References
 
No doubt in many tumour entities PET brings additional information to CT and MRI regarding tumour extension. PET/CT/MRI image fusion improves the precision of TVD in a significant number of patients. The changes are in both directions: additional tumour areas can be detected and included in the GTV, and biologically-negative areas can be identified and excluded from the GTV delineation. The precise definition of the gross tumour mass is an essential condition for dose escalation studies.

The development of new PET tracers offers the opportunity to visualise biological pathways with high impact upon radiation treatment response. The idea to use this type of biological information as specific targets for radiation therapy and to combine this information with the technique of IMRT, realising a biological-based dose painting, is fascinating and seems to be realisable. However, validating this hypothesis is a long way off, and further experimental and clinical studies are required.

Integration of PET data in TVD for RTP needs a radio-oncological point of view in understanding and utilising the information from biological imaging. Geometrical 3D localisation of the target plays a crucial role in high precision radiation therapy. Tumour morphology on PET should be compared with tumour extension on the radiological investigations and histological or pathological results. The accuracy of the PET/CT/MRI image fusion software has to be evaluated and validated for each new tracer.

The data available in the literature are insufficient to indicate the routine use of PET for TVD. This approach has to be further evaluated in clinical trials, which quantify its impact on patient outcome. However, the results of these studies will depend on many other aspects of the radiation treatment: patient positioning, organ motion, total dose and fractionation, additional systemic therapy, etc. One has to consider all these facets, otherwise there is a danger of producing false results and compromising the method.

A balance between our desire to know more about tumour biology, to have a real impact on our patients and costs should be kept in mind.


   References
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 Discussion
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 References
 

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