Egesta Lopci • Mink S. Schinkelshoek • Filippo Alongi • Lidija Antunovic • Stefano Arcangeli • Anna Maria Ascolese • Valentino Bettinardi • Francesca Lobefalo • Pietro Mancosu • Giovanna Pepe • Giacomo Reggiori • Marcello Rodari • Pietro Rossi • Giovanni Tosi • Angelo Tozzi • Marta Scorsetti • Arturo Chiti
TARGET IDENTIFICATION AND TUMOR DELINEATION
Radiotherapy (RT) is an important means of treatment in current oncology practice. In recent decades, a growing interest has emerged in the planning of RT. To target the tumor tissue and leave the healthy tissue out of the radiation beam, specific tumor identification and delineation are needed. In the early years of RT use in management of cancer patients, few tools were available to readily identify the total extent of the tumor and the growth of tumor cells into adjacent healthy tissues. By means of planar x-rays, oncologists estimated the tumor size and location in a two-dimensional (2D) view. Evaluating growth in the third dimension was not possible, so margins were vast to correct for this lack of information. Moreover, dose calculations were done by hand based only on visual information, so that the possibility of specifying tumor dose distribution was limited.
With the new imaging tools that became available in recent years, the possibilities to distinguish between tumor tissue and adjacent healthy tissue broadened. More recently, the addition of a third dimension to imaging modalities eliminated the problem of irregular growth and consequently reduced dose administration to healthy tissue. Along with the improvement in imaging equipment, software was introduced to calculate the radiation dose distribution based on the imaging. This proved to be a valuable tool to further reduce the damage to healthy tissue adjacent to the tumor and beyond. Imaging plays an increasing role in the planning stage of RT treatment of patients. Several modalities are used to identify and delineate the tumor volume for RT. The actual process of delineating the tumor involves the assessment of three different volumes. First, based on the image the gross tumor volume (GTV) is depicted. This volume contains the location and extent of the tumor as far as it is visible or palpable. Second, the clinical target volume (CTV) is composed. This volume contains the GTV and the microscopic tumor outgrowth that is not incorporated in the GTV, but should be eliminated as well. Third, the planning target volume (PTV) is a construct which takes into account that RT is not as precise as targeting the CTV only, because of several patient-related as well as procedure-related factors. Examples of these factors are movement of the patient during the procedure, motion of the organs of the patient between the planning and the actual therapy or during therapy itself, and differences between placement of the patient between the planning procedure and the RT procedure.1,2
Based on the PTV, a computer program calculates the dose and placement of the beams for the RT procedure. This leads to the treatment that administers high doses of radiation to tumor cells while sparing healthy tissue close to the tumor. In this way, it is possible to establish a steep radiation gradient at the edges of the PTV, leading to a reduction of side effects of the RT. Intensity-modulated radiation therapy (IMRT) is an example of a further refinement of dose administration. In this technique, implemented in clinical practice approximately 10 years ago, it is possible to vary the radiation flux in one single beam, so that spatial distribution of the radiation dose is more flexible than before. This allows for further sparing of the tissues surrounding the tumor, while being able to increase the dose administered to the cancer cells.3
Even though tumor identification and delineation are a result of the newer technologies, there are remaining problems that impact RT planning. Most modalities do not provide functional information, so that a distinction between actively dividing, for example, hypoxic tumor tissue and healthy tissue is difficult although tissue densities are similar. Furthermore, patients can gain or lose weight in the interval between treatment planning and actual RT. During that period, tissues borders could change significantly, because of tumor growth or other factors.4 The potential to circumvent these practical problems is growing, especially by correcting for different computer programs. At this time, a margin around the tumor tissue is still necessary.
The most frequently used technique for RT planning is computed tomography (CT) and the role of other modalities, such as magnetic resonance (MR) and positron emission tomography (PET), is increasing. In many tumor types, co-registration of two or more modalities is used, because the combination may improve tumor staging, identification and delineation, and RT planning. An improvement in the accuracy of tumor identification and delineation may in turn lead to a decrease in inter- and intraobserver variability. This section describes the several modalities used for RT planning as well as their advantages and disadvantages for tumor detection, staging, and delineation of the tumor.
The role of CT in RT planning is historically very important. In many tumors, a CT scan is used as the basis to delineate the tumor. The reasons for this pivotal role of CT are the excellent image resolution of this modality and the tissue attenuation information that can be used for RT planning. Other advantages of this modality are the wide availability and the low costs compared with the other modalities discussed here. Nevertheless, there are certain problems that impair the image quality and accuracy of target-volume delineation in RT planning.
Planning is often carried out manually, which is still one of the major courses of inaccuracy of tumor delineation, even if the delineation is done by experienced clinicians. Many studies show that inter-observer variation is a serious problem in delineating tumor tissue for RT.5,6 Another problem arises because it is difficult to distinguish tumor tissue from healthy tissue if the densities of both tissues are similar. This might result in failure to identify some tumors. Contrast media enhance the ability of CT to distinguish tissues from each other.7 Furthermore, the ionizing radiation delivered by CT is a burden to the patient. Whereas RT should deliver the dose exclusively to the tumor, CT radiates the whole body, so that there is radiation exposure of uninvolved tissues that may impose additional theoretical risks, especially in younger patients.8
Magnetic Resonance Imaging
Even though MR imaging renders excellent soft tissue contrast and circumvents the problem encountered in the CT of artifacts associated with dental fillings and metal prostheses, there are some features of this modality that limit its use as a single means of RT planning. MR does not give radiation attenuation information needed for dose distribution calculations in RT planning. Moreover, geometric distortions are important sources of position errors of MR.
These distortions are caused by inhomogeneities of the main magnetic field and nonlinearity in the applied magnetic field gradients. At the edges of the field of view (FOV), the distortions are mostly greatest.
With increasing use of CT–MR fusion in RT planning of different tumors, the question arises whether it is possible to base RT on MR alone. Jonsson et al.9 have assessed this idea to lower costs and decrease patient dose. The main limitations to this approach appear to be the geometrical distortions and lack of tissue attenuation information in MR. Attenuation density information is needed for RT dose calculations. Jonsson et al.9 investigated if the accuracy of dose calculation differs from the dose calculation achieved by CT-derived attenuation information. If the differences are negligible, MR without CT for RT planning would be possible. These differences were assessed in different tissues and tumor types. Jonsson et al.9 concluded that dose calculation accuracy is not a limiting factor to the sole use of MR as a means of RT planning. CT is no longer absolutely necessary in RT planning of cancer.
Beavis et al.10 address the same problem in their study on the possibility of using MR alone as the modality for RT planning in brain tumors. In RT planning, the better soft tissue delineation and definition of organs at risk are advantages. However, the disadvantages of a lack of tissue attenuation information and geometric distortions stood in the way of using only MR for RT planning. Therefore, conventional practice is CT–MR fusion, because adding CT to the procedure diminishes the disadvantages of MR alone. In this study, Beavis et al. took electron density as being homogeneous throughout the brain. They assumed that this lack of tissue attenuation information would not significantly change dose distribution to the tumor. They reached the conclusion that the uncertainty caused by the lack of information was acceptable and did not outweigh the advantages of eliminating CT in RT planning.
Stanescu et al.11 also tried to establish a way to use MR only in the RT planning of intracranial lesions. They used bulk density assignment, as Jonsson did, and atlas-based software to diminish the problem of lack of attenuation density information and by using software to correct for geometrical distortion. After these adjustments, they compared the planning volumes of CT–MR with those acquired by MR only. They were comparable in shape and showed an acceptable difference in location and size. This means that MR alone can be used in RT planning in patients with brain tumors.
The superior soft tissue contrast is thought to add valuable information to the information acquired by CT, so that tumor tissue could be delineated more accurately, thereby sparing the adjacent healthy tissue. Even though the increased soft tissue contrast could be a valuable addition in delineating every tumor type, the use of MR in RT planning has been more intensively studied in only certain tumor types. This depends on the importance of adjacent healthy tissues, such as the reproductive system in prostate, cervical, and rectal cancer and the spinal cord and the brain in head and neck and brain tumors or because the conventional planning CT is evidentially suboptimal.12–14
Positron Emission Tomography
In RT planning, a role for PET in adding functional information to the anatomical information of CT and MR leads to a better definition of tumor volume and detection of physiologically distinct areas in the tumor. Brændengen et al.15 conducted a study in which they assessed the influence of 18F-FDG PET-CT on GTV size, shape, and localization compared to the conventional way of defining GTV in rectal cancer with MR and CT. The advantage of using 18F-FDG PET-CT was thought to be that functional information would now be added to the delineation process. Brændengen et al. wanted to measure the advantage that this new modality might offer. Their results showed that 18F-FDG PET-CT rendered a smaller GTV when used alone but as an addition to conventional RT planning, it increased the GTV by adding undetected tumor tissue to the conventional GTV. It is still uncertain if this information has any value for treatment decisions or disease outcome. Brændengen et al. concluded that until the difference 18F-FDG PET-CT makes is found to have an effect on clinical choices or outcome, the use of 18F-FDG PET-CT should not be advised.
By comparing CTVs acquired by either CT or 18F-FDG PET-CT in patients with several tumor types, Marta et al.16 tried to answer the question if 18F-FDG PET-CT really is of additional value when compared with CT alone. They could only detect a significant difference in CTV in patients with lymphoma, lung or head and neck tumors. This led to the conclusion that more research is needed on this topic to provide firm evidence for the additional value of adding 18F-FDG PET-CT to conventional RT planning with CT in these tumors.
Muijs et al.17 conducted a systematic review on the role of 18F-FDG PET-CT on RT planning in patients with esophageal cancer. They focused on tumor detection, delineation, and treatment outcome of the patients after RT planned on the basis of 18F-FDG PET-CT. The use of FDG PET in tumor detection seems to be justified, because both sensitivity and specificity are sufficiently high to detect most tumors. Tumor delineation is significantly different in 18F-FDG PET-CT compared to conventional planning CT, but evidence is limited, so that definite conclusions are hard to draw. When Muijs et al. did their review, there was no evidence yet about the increased survival or other outcome measures following RT planning with 18F-FDG PET-CT. They concluded that it is not yet justified to put 18F-FDG PET-CT into everyday practice of esophageal cancer treatment, because evidence is lacking. More research on the use of this modality in RT planning of patients with esophageal cancer is needed.
These studies show that the role of FDG PET in RT planning is the object of research in many different cancer types. This specific radiopharmaceutical can be broadly used because its accumulation is based on enhanced glycolysis, a property of many different tumors. Because of the slightly different structure compared to glucose, this compound could not be degraded in nor exported out of the cell, leading to its entrapment in the tumor cell.18
Another radiopharmaceutical used is 11C-CHO, a tracer of lipid metabolism. The compound enters the cell via the choline transport system and is processed in the cell to eventually become a phospholipid for cell membrane construction. This step is very important in tumor cells, because for proliferation new cell membranes should be synthesized. 18F-fluoroethylcholine (FEC) and 18F-fluoromethylcholine (FMC) are similar radiopharmaceuticals. These markers seem to have some value in RT planning in patients with prostate cancer, as the following studies conclude.
It is assumed that 11C-CHO PET-CT is a modality in the field of nuclear medicine that could be particularly valuable in detecting and defining the borders of prostate tumor cells. Souvatzoglou et al.19 evaluated the role of 11C-CHO PET-CT in RT planning in patients with recurrent prostate cancer. They measured the incidence of 11C-CHO PET-CT positive findings in these patients and compared the differences in PTV between conventional planning CT and 11C-CHO PET-CT. This research question is of specific interest because neither CT nor MR nor bone scintigraphy seemed to be able to detect low-volume metastases as a marker for recurrent disease. Because of the functional information that 11C-CHO PET-CT gives, it was hypothesized that this modality would improve the definition of tumor tissue in patients with recurrent prostate cancer. 11C-CHO PET-CT showed an increase in PTV in 13% of the cases. The conclusion drawn from this result is that 11C-CHO PET-CT can be used to individualize treatment in these patients, but that its use should be further investigated before it can be used in conventional clinical practice.
In another study on prostate cancer, Würschmidt et al.20 evaluate the use of 18F-FEC PET-CT in staging and RT planning in primary and recurrent prostate cancer. Like Souvatzoglou et al.,19 Würschmidt et al. hypothesized that the additional functional information supplied by FEC PET-CT would lead to a more accurate definition of tumor volume and the possibility of dose escalation to tumor sites while sparing adjacent healthy tissues. They focused on clinical outcome by monitoring the (disease free) survival of patients participating in this study. Their results showed a possibility to escalate doses administered to the tumor though avoiding radiation damage to normal tissues. Even a significant part of the patients with tumor invasion of lymph nodes, detected during RT planning by FEC PET-CT, was still disease free at the end of the study. This underlines the value of FEC PET-CT in RT planning and on the outcome of treatment.
Amino acids are other possible compounds for RT planning. Tumor cells proliferate rapidly, so they need relatively large amounts of amino acids to synthesize proteins for new cells.
L-[methyl-11C] methionine (11C-MET), O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) and 18F-FDOPA are some examples of this type of radiopharmaceuticals. These markers measure amino acid uptake which is high in tumor cells compared to healthy cells. Currently, these amino acids are mainly used for brain tumor RT planning, even though other applications are under evaluation. Astner et al.21 conducted a study on the use of MET PET in meningiomas.
The use of 11C-MET PET for RT planning in skull base meningiomas is thought to visualize tumor cells, because the uptake of this particular amino acid is much higher in metabolically active cells like meningioma cells, compared with the gray and white matter adjacent to those tumor cells. Astner et al.21 assess the effect of adding MET PET to the conventional combined CT–MR RT planning in skull base meningiomas. Therefore, they measured GTV in both CT–MR and MET PET. These images were co-registered and GTVs were compared. Their results showed that MET PET can both increase and decrease GTV, depending on the site of the tumor. Either way addition of MET PET led to a more accurate and precise delineation of the tumor volume.
Although all radiopharmaceuticals discussed above are only based on the distinction between tumor and nontumor cells, there is a growing interest in radiopharmaceuticals that describe the tumor cells they target. One example of this approach is the hypoxia markers, such as 18F-FMISO, 18F-FAZA, and 64Cu-ATSM. They become trapped in hypoxic cells in many different ways, but seem to reflect the O2 status of tumor cells quite accurately. Many more of these kinds of markers based on a specific feature of a tumor cell (like also 68Ga-DOTATOC) are currently developed. The following two studies illustrate the place of a hypoxia marker and 68Ga-DOTATOC in RT planning of different tumors. With the development of new and more specific markers, it becomes possible to individualize cancer treatment.
Because none of the modalities described above shows a perfect resolution, contrast, and electron density, their combination in RT planning is increasing. Many of the studies presented above already make use of RT planning with different modalities.
The use of multiple modalities has the benefit of using the advantages of each modality while compensating for each drawback. However, there are some disadvantages related to the use of more than one modality. To be able to have a single image for inspection co-registration of separate images is needed. This asks for identical patient placement in both modalities of RT planning scans and in RT itself. Differences in positioning the patient lead to further inaccuracy of the final image. PET-CT has the advantage that both scans can be executed in the same session, without moving the patient.7 Another problem arises because computer programs fuse the images acquired by different scans. These programs insert another error-prone procedure to the total process of RT planning.3
PET-CT and PET-MR in Radiotherapy Planning
Most commonly PET-CT imaging is performed in the whole-body mode with the CT and complementary PET scan covering a coaxial scan range from the head/neck to the upper thighs.
With a patient displacement error still negligible (<0.5 mm), PET-CT offers anatomical and functional images that can guide radiation therapy planning. A flat radiation therapy pallet is mounted on the top of the PET-CT patient pallet and allows patient positioning as in the actual radiation treatment of the patient. Last but not the least, the new PET-CT scanners have an increased bore diameter that allows reproducible patient positioning with standard RT-positioning aids during the diagnostic, pretreatment PET-CT scan. The choice of a reconstruction algorithm with its parameters is a compromise that can affect the presence of artifacts, the SNR, the resolution, the quantification accuracy, and the reconstruction time (i.e., quantification is crucial in standardized uptake value (SUV) evaluation, high resolution is necessary for accurate target delineation for RT). A trade-off between high resolution and high SNR has to be done for heterogeneity assessment and dose painting; in any case, a low-quality data also dramatically influences the best reconstruction protocol. Moreover, in modern PET-CT scanners, gated acquisitions minimize motion blur.
Currently, anatomical image data guide radiation treatment planning. Nevertheless, functional imaging supplies complementary information to anatomical imaging in certain situation in which the latter ones are inadequate such as, for example, in the distinction between necrotic and viable tumor volume. In these situations, PET-CT can help in the delineation of biological target volume (BTV) or GTV. The reason for integrating functional imaging in the GTV definition is its higher sensitivity and specificity for malignant tissues. The GTV can be delineated on the RT treatment planning environment or on the nuclear medicine workstation; in the first case, the anatomical and biologic imaging datasets are transferred as DICOM datasets. In the second case, data are transferred to the treatment planning system as a set of regions of interest (ROI) forming a volume of interest (VOI) together with the DICOM image objects. The data transfer between the nuclear medicine imaging workstation and RT planning modalities can also be done through a hospital PACS. There are several modes (manual or automatic) for target volume contouring on PET images. A threshold-based method is supported by most systems, where the actual VOIs can be defined with respect to the maximum specific uptake value or maximum activity in a predefined VOI-mask.
PET/MR gives the opportunity to cover a wide range of imaging from morphology (MR) to physiology (MR + PET) and biochemistry (PET), and comprises a PET scanner and an MR scanner; both machines have a 3-T magnetic field. The attenuation correction for PET is directly based on MR images. Simultaneous imaging has a great improvement on the spatial correlation; it seems to be very helpful for radiation treatment planning. At the moment, these scanners are few in number around the world, so their use is still in the research stage.
PET Imaging in Stereotactic Body Radiotherapy
Stereotactic body radiotherapy (SBRT) is an emerging technology that allows precise delivery of high doses of radiation with a sharp dose gradient in selected patients. It is defined by prescription and precise delivery of a limited number of fractions (typically less than 5) to treat small treatment volumes with high doses of radiation. Originally, stereotaxy as applied to radiation was pioneered by Leksel et al.22 to treat intracranial tumors using a framed positioning system for the Gamma Knife Radiosurgical System (Elekta Instruments AB, Stockholm, Sweden). More recent technologies have adapted linear accelerators to similarly allow precise radiation delivery to extracranial sites using a frameless system. SBRT requires a high degree of precision in all aspects of treatment planning and delivery to minimize toxicity to adjacent structures.23
However, many questions still remain regarding the utilization of PET-CT in conjunction with SBRT. Ongoing research tries to shed light on the utility of PET and/or PET-CT in treatment planning, the appropriate interval to image patients after treatment, and the relationship between PET-CT and clinical outcomes, among other topics. In this section, we provide an overview of SBRT, explore the relationship between PET and SBRT in a variety of sites, and summarize the evidence on these topics.
In the conventional fractionated treatment, PET has demonstrated numerous uses. Studies have assessed its potential for more precise target delineation and its role in treatment follow-up to detect recurrence.24,25 In addition, PET has the potential to assess response and serve as an early surrogate of treatment failure. This may be particularly important in operable patients receiving SBRT in whom PET enables earlier detection of failure and, thus, could decrease the doctor’s delay for surgical salvage therapy.26
However, SBRT differs in many respects from conventional fractionated RT and this may present both novel applications and challenges for PET imaging. SBRT delivers large doses of radiation during each fraction, making precise target delineation essential. The ability of PET to distinguish malignant from atelectatic or normal tissue may be used to decrease treatment volumes and reduce adverse effects. Furthermore, the radiobiology of cell death in SBRT with high doses per fraction may differ from conventional fractionated RT, possibly affecting PET uptake in irradiated tissue. Referring to the literature on conventional fractionated radiation therapy, a few salient issues regarding the utility of PET for treatment planning for SBRT applications emerge. These include the differences in tumor edge determination with PET and CT-based treatment plans and the effect of respiration on image quality and fusion for PET-CT. These issues will be briefly discussed here.
One potential source of error in using the two imaging modalities lies within the technique and fusion of the two types of images. Unlike the rapidly acquired CT image, PET images may take several minutes during which the patient is breathing. This may result in image blurring, degraded contrast, and an overestimation of volume, thereby potentially interfering with the accurate detection of tumor edges required for SBRT.27,28 In light of the precise tumor definition required for SBRT applications, single-gantry PET-CT imaging using gating or breath-holding techniques may be critical for increasing the accuracy of tumor edges for SBRT application.29
Studies have also assessed the accuracy and correlation of PET-based gross tumor volume (GTV; GTV-PET) with CT-based GTV (GTV-CT) planning in conventional fractionated radiation therapy. Work at Emory in head and neck patients receiving IMRT revealed GTV-PET was smaller than GTV-CT in most cases (75%), but the GTV-PET was not necessarily encompassed by the GTV-CT. This resulted in insufficient dose delivery in portions of the GTV-PET in 25% of cases.30
Another area of concern with PET-CT and SBRT is the appropriate management when SUV is low or intermediate. In this situation, the clinician is faced with the decision to either treat or pursue diagnostics. Given the high doses and conformal nature of SBRT, we believe that histologic evaluation of areas with intermediate SUV should be executed whenever possible prior to treatment.
Certainly, using PET for treatment planning for SBRT requires a degree of precision that exceeds the requirement for conventional fractionated radiation therapy. Incremental advances to facilitate improved co-registration of images, minimize respiratory artifacts, and determine optimal PET SUV thresholds will certainly be of tremendous value to those looking forward to PET-CT–based treatment planning for SBRT.
In summary, SBRT is a new radiation treatment paradigm that enables precise delivery of high-dose radiation in a hypofractionated schedule. A number of treatment platforms are available and although studies have not compared outcomes between platforms, our experience has demonstrated outcomes to be platform independent. SBRT requires accurate tumor detection and delineation, and in many sites PET appears to be quite useful in accomplishing this prerequisite. PET can frequently differentiate radiation necrosis from tumor recurrence and identify smaller tumor deposits when compared with CT, which may significantly modify treatment plans. In most studies, pretreatment PET was not well correlated with survival or other outcome measures. However, in follow-up, PET may offer important prognostic information. Further research in the field and larger study samples are needed to more accurately define the role of PET in SBRT.
OTHER MODALITIES AND FUTURE PERSPECTIVES
Even though PET is extensively discussed here, MR spectroscopy and single photon emission computed tomography (SPECT) are also modalities that have the ability to depict the biologic characteristics of tumor cells. The research done on the role of these two modalities is very limited and it is improbable that those will overtake the leading role PET has in adding functional information to RT planning.
The role of CT in RT planning is still most important, but the addition of MR and PET have the potential to increase the accuracy, precision of tumor-volume definition (TVD), and the possibility to show the diversity in tumor types. Even though first studies show promising results, a lack of randomized clinical trials and large numbers of patients included in these trials still keeps these modalities from establishing a place in conventional clinical practice. Another problem is the absence of measurements of effects on clinical outcome. Nonetheless, there is a strong rationale for the successful use of these techniques in radiation oncology.
The new PET markers that are developed provide the possibility to further individualize RT by visualizing the biologic diversity of tumor cells in the tumor. With this information, an approach with increased dose administration to relatively therapy resistant tumor parts comes into sight. The same need for extensive prospective studies counts for these PET markers before they could be implemented in conventional clinical practice.
CURRENT RADIATION THERAPY SYSTEMS
The basic principle of external beam RT is to deliver one or several beams of high-energy x-rays or electrons to a patient’s tumor. Beams are generated outside the patient by means of a linear accelerator and then targeted at the tumor site. Though the working principle of the linear accelerator has not changed since the beginning, the evolution of RT in the last 10 years has seen the advent of several systems with different geometrical principles (e.g., isocentric, nonisocentric, etc.) that have greatly extended the potentialities of this technique.
Today, there is a wide variety of image-guidance systems available that can give different information about the patient anatomy and positioning according to the different treatment devices considered. Specifically, point-based imaging systems, such as the ones based on detecting locations of implanted electromagnetic transponders or photon emission seeds, provide location of a single point within the patient. Also, x-ray planar imaging, including floor-mounted or gantry-mounted kilovoltage (kV) images, operated in radiographic or fluoroscopic mode or megavoltage (MV) images obtained via electronic portal imaging devices, generates a 2D intensity array. More recently, in-room volumetric imaging systems, such as MV CT, kV, and MV cone-beam CT, have provided superior volumetric images of patient geometry.
Linac and Cobalt
Medical linear accelerators (linacs) and cobalt RT units are used in external-beam radiation therapy to treat cancer. Though the technique used to produce γ-ray photons is different, linacs can be considered the evolution of cobalt RT units. The reason is that linacs operate with an isocentric technique just as cobalt units; the main differences are the higher photon energies achievable with linacs and the absence of a radioactive source with all the related radiation protection and dosimetric complications. Cobalt units and low-energy linacs are used primarily to treat bone cancer and tumors of the head, neck, and breast. High-energy linacs are used to treat deep-seated neoplasms and tumors of the pelvis and thorax. Nowadays cobalt RT units are almost entirely being substituted by linacs in modern centers but are still used, especially in developing countries because of the lower costs and the simpler utilization and maintenance.
Most of the linear accelerators currently produced are constructed so that the radiation source can rotate around a horizontal axis. As the gantry rotates, the collimator axis (supposed coincident with the central axis of the beam) moves in a vertical plane. The point of intersection of the collimator axis and the axis of rotation of the gantry is known as the isocenter. These units are suitable for isocentric treatmenttechniques in which beams are directed from different directions but intersect at the same point, the isocenter, placed inside the patient. Imaging can be performed by either exploiting the treatment beam with appropriate detectors (MV-imaging) or supplying the RT unit with an x-ray tube and a dedicated detector that moves jointly with the gantry (kV-imaging). The modern linacs usually use both these techniques together to increase the treatment accuracy. Radiation therapists can use 2D digital radiographies to verify or correct pretreatment setup by using anatomy match or marker match functions. Soft tissue-based image-guided radiotherapy (IGRT) is currently replacing 2D verification and frame-based intra- and extracranial stereotaxy.
The CyberKnife stereotactic radiosurgery system was developed by Accuray Inc. (Sunnyvale, CA, USA) and is a device designed for robotic image-guided stereotactic radiosurgery and RT throughout the whole body. Typical CyberKnife applications are the treatment of intracranial lesions close to critical structures that require small margins (≤2 mm).
The equipment is designed to be a purpose-built IGRT system, to deliver IMRT while also being able to verify the setup of the patient and, in the future, the dose delivered during treatment. The helical tomotherapy machine can be described as a combination of a helical CT scanner and a linear accelerator. The radiation unit is a linac that combines fan beam delivery in a continuously rotating gantry, with binary multileaf collimators that allow IMRT.
The American Brachytherapy Society (ABS) endorses the use of brachytherapy as an integral component of the definitive treatment of locally advanced cervical cancer (LACC). Several studies have shown decreased recurrence rates and increased survival when brachytherapy is a component of treatment.31,32 Patients selected for brachytherapy may have any stage of cervical cancer. In particular, brachytherapy is indicated after external beam for all cases of locally advanced disease (stages IB2eIVA); brachytherapy alone may be used as a primary treatment for those with early stage disease (stage IAeIB1).
Patient setup has always been a very important part of RT and essential for the success of treatment. The use of PET in radiation oncology requires the use of dedicated equipment for scanners and their rooms. Therefore a new procedure, called hot setup, has been introduced as an addition to the traditional procedure. There are some important differences between both the procedures: The cold setup procedure is a series of actions aimed at preparing containing systems and the acquisition of a target volume and its coordinates (x, y, and z), whereas hot setup focuses on patient centering and the acquisition of images to determine the BTV. The hot setup procedure takes an average 20 to 25 minutes which is more or less the same as the duration of a session of RT.
As mentioned before, the room where the PET scanner is placed is equipped with devices specifically used for setup procedures. There are basic devices without which it would not be possible to execute hot setup procedures; they are dependent on the room user; the laser tracking system fixed to floor, walls, or ceiling; and a patient bedtop cover as part of the scanner.
To further ensure the comfort of the patient, it is very important to lay down the patient in an easily achievable and natural position (compatible with the position required by the treatment) and to make sure that the masks or thermoplastic sheets are shaped perfectly over the surface of the skin.
PET scanning consists of three steps: Radiopharmaceutical administration, uptake, and image acquisition. The time these steps take depends on the radiopharmaceutical used.
During the PET-CT procedure, breathholding is not feasible, because of the long acquisition time needed to complete a whole-body PET study (1 to 3 min/FOV × 6 to 8 FOV). Therefore, the study must be performed in a free-breathing condition. During the scan, the patient advances through many full breathing cycles and, consequently, the reconstructed PET images are somewhat blurred, because of the internal motion induced by breathing, especially in the case of thorax and upper abdomen organs. Whereas cardiac motion has important local effects on the heart itself and on areas proximal to the heart, respiratory motion affects the imaging for the majority of the body extent, from the thorax to the abdomen (including heart, lungs, liver, pancreas, and kidneys). It has been reported that organ displacements 5, 5, and 30 mm, or even more, may occur in anterior–posterior, left–right, and superior–inferior directions, respectively during normal breathing.
Motion produces two distinct challenges for PET/CT. First, it blurs PET emission data. In addition, the fast acquisition of modern multi-slice CT produces images that represent a specific moment within the respiratory cycle, whereas the much slower acquisition time of PET produces an image that represents the average of many respiratory cycles. This mismatch in phases can produce artifacts as shown in Figures 29.1–29.3, for CT on mobile phantom, PET on mobile phantom, and PET on patients, respectively.
These movements lead to the spread of activity distribution— in particular, for the focal lesions—resulting in inaccurate radioactivity concentration quantification (i.e., SUV), and in an erroneous estimation of the lesion shape and volume. Therefore, it is self-evident that limitations in PET image quality and quantitative accuracy caused by motion explain the growing interest in studying the effects of breathing and in developing methods to control and compensate for patient motion. The existing proposed methodologies for respiratory motion compensation involve the use of respiratory synchronized or respiratory gated acquisitions. A large number of studies have been devoted to the development of respiratory gating protocols for PET and CT imaging.
Researchers have investigated a large number of different respiration monitoring systems, including a transducer and an impedance ECG monitor measuring changes in abdominal or thoracic circumference, a thermistor measuring the temperature of circulating air during patient respiration, a spirometer measuring respiratory flow, or systems tracking the displacement of infrared reflective markers in the patient chest. With the exception of the spirometer and the thermistor, the majority of these systems provide a respiratory signal through the measurement of the displacement of the thoracic cage. The majority of them lead to an accurate and reproducible respiratory signal.
FIGURE 29.1. CT scans (64-slice) of a moving sphere over an ellipsoid path (motion of 5/10/30 mm in anterior–posterior, left–right, and cranial–caudal directions, respectively, over a breathing cycle of 2.5 seconds). The scans were acquired consecutively using standard helical parameters without considering the phantom motion. The same coordinates are used for the three images, revealing motion artifacts. Data courtesy of Hospital Sao Rafael, Salvador de Bahia, Brazil.
Respiratory gated four-dimensional (4D) PET/CT acquisition techniques have been proposed to reduce the unwanted blurring on PET images and to improve the spatial matching between PET and CT images. Briefly, a 4D-PET/CT acquisition protocol consists of a 4D-CT and a 4D-PET acquisition synchronized to the patient’s breathing cycle. After the acquisition, both 4D-CT and 4D-PET data are sorted, divided, and processed to generate new sets of images (phases), each of which is representative of a specific moment of the patient’s respiratory cycle. Therefore, the aim of 4D-PET/CT techniques is, in fact, to produce “motion free” and well-matched PET and CT images corresponding to specific phases of the patient’s respiratory cycle.
There are two techniques to acquire motion-free CT images: Prospective and retrospective 4D-CT methods. In the prospective 4D-CT technique, data are selectively acquired during a time window within the breathing cycle, corresponding to a specific respiratory phase. When using the prospective 4D-CT technique, the anatomical volume is depicted in a single respiratory phase, corresponding to a specific moment of the breathing cycle, without information on the whole respiratory motion of the organ/lesion under examination. Prospective 4D-CT protocols are commonly used, independently from the association with PET or 4D-PET, for RTx applications performed in gated mode over the same phase (e.g., end-expiration or end-inspiration).
The retrospective 4D-CT technique requires the acquisition of data at each table position (over the same anatomical region) for the duration of at least one complete patient’s breathing cycle. Once reconstructed, the 4D-CT images are sorted in a number of phases (e.g., 10 to 20), each representative of the anatomical volume in a specific moment of the patient’s breathing cycle. Contrary to the prospective technique, the retrospective 4D-CT technique, by producing a set of images representative of the whole breathing cycle, allows the detection of the complete organ/lesion motion during respiration. 4D-CT acquired using a retrospective protocol, despite the higher radiation dose, is preferable as it allows detection of the complete organ/lesion motion and the attenuation correction of PET images with CT phase-matched images. Once generated, the 4D-CT phases can be used for TVD. The contour of the target in each of the 4D-CT phases represents the GTV in different moments of the patient’s breathing cycle. The combination of the GTVs gives the internal target volume (ITV) representing the volume of space encompassing the motion of the tumor because of the patient’s respiration. Figure 29.4 shows difference in volumes for target definition, considering the standard approach based on free-breathing CT or the 4D-CT acquisition technique.
FIGURE 29.2. PET/CT images of a sphere phantom. Left: The sphere was not moved in both CT and PET acquisitions. Center and right: The phantom was moved over cranial–caudal direction (15 mm) over a period of 6 seconds, inducing mismatch between PET and free-breathing CTs.
FIGURE 29.3. Whole-body PET images demonstrating artifacts at the level of the diaphragm as a result of respiratory motion using CT transmission maps used for attenuation correction. Left: CT acquired at end inspiration breath-hold. Right: CT acquired at end expiration breath-hold. Data courtesy of Visvikis D, Lamare F, Bruyant P, et al. Respiratory motion in positron emission tomography for oncology applications: Problems and solutions. Nucl Instrum Meth A. 2006;569:453–457.
Further data processing of 4D-CT images, to be used for TVD of lung cancer, consist of the generation of maximum intensity projections (MIP) or an averaged (AVE) set of CT images. Briefly, in an MIP image each voxel reflects the greatest density values throughout all the 4D-CT phases, whereas in an AVE image each voxel is obtained as the arithmetic mean among the 4D-CT phases. Because of this effect, the contouring of AVE images may underestimate the volume of space encompassing the tumor motion. Furthermore, MIP and AVE images have to be carefully evaluated in all the regions where the background and the tumor present similar Hounsfield numbers (e.g., tumors located closed to the diaphragm, nodal volumes in the mediastinum). Finally, both MIP and AVE images may be used only for lung studies.
4D-PET Data Acquisition
Counts collected during a 4D-PET scan are subdivided among the image phases representative of a respiratory cycle. The number of phases has to be sufficiently high to produce motion-free or almost motion-free images. A main limitation in 4D-PET is thus represented by the statistical noise in the individual phases. As a result, the total acquisition time of the 4D-PET scan has to be longer than that of the conventional (non-4D) scans to collect enough counts to balance statistical noise and motion compensation in each image phase. 4D-PET studies should be performed in three-dimensional (3D) list mode, to take full advantage of the higher sensitivity of the 3D acquisition mode as well as of the retrospective data postprocessing protocols flexibility. The suggested number of phases is six, as this represents a good compromise between statistical noise and motion compensation.
The acquisition time for an RG 4D-PET (per single FOV) can be estimated as the product of the time per bed position, in a conventional PET scan, and the established number of phases. In a 4D PET/CT study, the number of 4D-CT and 4D-PET phases has to be the same. Noise control in 4D-PET is also important to allow quantitative or semiquantitative (SUV) assessment of radioactivity concentration.
Head and Neck Cancer
Head and neck cancer (HNC) is a general description that is used for a number of different types of malignant tumors that occur in the mouth, throat, sinuses, nasal spaces, the larynx, salivary glands, and the cervical lymph nodes. Tumors of the brain or thyroid are usually not considered to be a part of this general category of tumors. HNCs may spread to lymph nodes in the neck, and to other parts of the body.
The cure of HNC, especially in advanced disease, still remains poor.33 Because of this poor outcome, there have been efforts to improve outcome through the use of targeted agents, new radiation techniques as well as new types of diagnostic imaging.34–36 Because of the highly conformal dose distribution and steep dose gradients used in IMRT, knowledge about the localization and boundaries of the primary tumor and of the cervical lymph node metastases is of increasing importance.
FIGURE 29.4. Bar graph showing mean three-dimensional volume and mean four-dimensional volume of lung lesions acquired with standard spiral CT (for 3D case) and 4D-CT techniques. The percentage difference between them is specified on top of the bars for each lesion. Data courtesy of Aristophanous M, Berbeco RI, Killoran JH, et al. Clinical utility of 4D FDG-PET/CT scans in radiation treatment planning. Int J Radiat Oncol Biol Phys. 2012;82:e99–e105.
Delineation of Radiation Therapy Target Volume in Head and Neck Squamous Cell Carcinoma
In head and neck squamous cell carcinoma (HNSCC), constituting 90% of all head and neck tumors, delineation is usually executed with planning CT. Additional value of MR has yet not been shown in clinical studies.37 CT and MR both seem to be suboptimal in delineating tumor volume. That is why there is a growing interest in the role of PET in delineating the tumor. Potential advantages are the reduction of inter-observer variability and GTV size, while providing additional information about involved lymph nodes and tumor-resistant areas in the tumor. The low spatial resolution and the lack of a gold standard in signal segmentation are disadvantages of this modality.38 Multiple studies have assessed these hypotheses. Gardner et al.39 hypothesized that 18F-FDG PET-CT could detect those lymph nodes thereby ameliorating tumor-volume definition for RT. They compared organs at risk and GTV and evaluated later on if 18F-FDG PET-CT had really changed the planning volumes. They concluded that each modality added complementary information and improves treatment volume accuracy, but adding MR or 18F-FDG PET-CT to conventional CT is not beneficial if the tumor did not extend intracranially or if the patient had no contraindication for CT. The problem in many studies is that at the time of the study outcome measures are not yet available, so that changes in tumor volumes observed between different modalities could not be interpreted. Daisne et al.40 analyzed the surgical specimen of the tumor (pharyngolaryngeal squamous cell carcinoma [PLSCC]) visualized with CT, MR, and 18F-FDG PET-CT. Part of the patient population underwent total laryngectomy so that their surgical specimens could be examined as a control measure for the imaging modalities. The goal of the study was to compare the delineation of GTV in treatment planning of PLSCC between the three modalities. The GTVs acquired using 18F-FDG PET-CT were smaller than those acquired using the other two modalities, although the GTVs of all three modalities did not overlap completely. All three modalities overestimated the GTV compared to the surgical specimen. An interesting finding was that none of the modalities managed to visualize superficial tumor extensions. Overall, 18F-FDG PET-CT was the modality that approximated the GTV of the surgical specimen the closest.
There are several ways in which 18F-FDG PET-CT can alter RT planning: The target is only visible on PET, not on CT only; the tumor volume found by PET-CT is bigger than that found by CT only; specific hypermetabolic regions found by PET are apparent in the CT delineated tumor volume. All of these differences impact the RT planning and could thus alter clinical outcome. Scarfone et al.41 investigated the influence and accuracy of 18F-FDG PET-CT compared to conventional planning CT in head and neck tumors. Their results showed that PET could be helpful in identifying metabolically hyperactive sites for dose intensification. There was a difference in tumor volumes between both procedures, but it was not clear to what extent these alterations could be attributed to imperfections in the process of co-registration in 18F-FDG PET-CT. Even though these outcomes are promising, histologic validation and clinical studies are necessary before 18FDG PET-CT can find a place in conventional RT planning in HNSCC.38
Primary Tumor and Metastases in Cervical Nodes in Head and Neck Squamous Cell Carcinoma
Chang et al.42 evaluated the value of 18FDG PET in staging nasopharyngeal carcinoma (NPC). They concluded that 18FDG PET stages N and M status more accurately than the usual CT and MR. Lonneux et al.43 reported 18FDG PET improved both T and N and M in head and neck tumors and altered the management of 13.7% of patients taking part in their study. Another study by Kyzas, et al.,44 assessed the role of 18FDGPET in general staging, but also in patients with distant metastases and no cervical lymph node involvement. 18FDG PET showed high specificity and sensitivity in detecting the primary tumor, but failed to visualize the distant metastases in 50% of the patients.38
A multi-center study on 233 HNC patients prospectively compared therapeutic decisions based on conventional work-up (CT and MR) with those additionally performing a whole-body 18FDG PET scan. Functional imaging resulted in up- or downstaging of the lymph node status in 10% of patients (upstage in 16 patients and downstage in 7 patients). However, the detection on metastatic or additional disease had a greater impact on patient management.43
The value of 18FDG PET for the identification of lymph node metastases in nasopharyngeal is controversial. Chang et al.42 performed a retrospective analysis on 95 nasopharyngeal cancer patients and found little discrepancy between MR and FDG PET for neck node staging. In patients with advanced nodal disease, FDG PET may reveal distant metastases missed by all other conventional imaging modalities.
In summary, there is not a solid evidence to support the routine clinical application of FDG PET in the pretreatment evaluation of the lymph node status in patients with head and neck tumor, including patients with clinically negative neck. Other imaging methods appear to have similarly limited or even worse diagnostic performance in these patients. There is insufficient evidence to support the routine clinical application of FDG PET in the pretreatment identification of lymph node metastases. Thus, ultrasound-guided fine needle aspiration cytology still remains the gold standard.
Dose Escalation and Adaptive Radiotherapy in Head and Neck Squamous Cell Carcinoma
Arens et al.45 and Moule et al.46 investigated if the adaptive threshold method they used was beneficial for tumor delineation with a possibility for dose escalation and adaptive RT using FDG PET. Pretreatment tumor delineation seemed to be justified allowing higher doses to tumor volume without higher healthy tissue dose. However, the software used was not able to distinguish tumor tissue from adjacent healthy tissue during treatment so that adaptive RT was not possible. Geets et al.47 concluded in their study that FDG PET had a significant impact on dose distribution in pharyngolaryngeal tumors and could, therefore, prove useful in dose escalation strategies. In another study, Geets et al.37 assessed the impact of FDG PET on dose distribution and the impact of MR–CT during treatment on target-volume delineation and dose distribution. PTVs, GTVs, and CTVs were all smaller when executing FDG PET pretreatment and MR–CT during treatment leading to new avenues for dose escalation without exposing healthy tissue to higher doses.
Duprez et al.48 were the first to escalate doses based on adaptive methods of FDG PET imaging during radiotherapy. Their results showed that they could expose the shrinking target volume to higher doses without inducing adjacent tissue toxicity or increased side effects. The results of this study should be validated in larger prospective trials before it can be used in conventional clinical practice.
Hypoxia in Head and Neck Squamous Cell Carcinoma
One of the reasons for treatment failure in RT is the presence of low oxygen levels in the tumor tissue. First postulated by Thomlinson and Gray,49 the concept of hypoxia correlation with a worse outcome in solid tumors is nowadays a well-known fact, taken in serious consideration when planning the most appropriate therapeutic regimen in oncology. The underlying condition explaining tumor-resistance in the presence of hypoxia is in part explained by the fact that hypoxic tumors have a more aggressive phenotype, selected genetically throughout unstable cells within the hypoxic environment. Secondarily, the presence of hypoxia activates specific molecular pathways, responsible for new gene-expression and more independent cell survival mechanisms. The aggressiveness is then expressed either by increased incidence of distant metastases or with reduced response to current treatments, including radiation therapy.50,51 Moreover, hypoxic tissues are known to require up to three times the radiation dose usually applied in normo-oxygenated cells.52
There is growing interest in diagnosing hypoxic HNSCC before therapy in the hope of applying novel treatment strategies that may overcome resistance to conventional chemoradiation.53 Several tracers are developed to identify hypoxic tumor cells, so that they can be targeted for dose escalation. Some examples of these hypoxia markers are 18F-FMISO and 18F-FAZA. It is not yet clear to what extent these markers will differ in their clinical performance. Even more, the clinical value of characterizing the biologic features of tumor cells is still to be assessed. The potential utility of these and other tracers for targeting areas for dose painting could be evaluated in clinical studies and a growing interest is emerging on executing these kind of studies.54 Lee et al.55 examined the utility of 18F-FMISO PET–CT-guided IMRT. Their goal was to escalate doses to a maximum in hypoxic areas, visualized by the hypoxia marker. They showed that they were able to escalate doses to hypoxic areas without exceeding the normal tissue tolerance. Doses above normal tissue tolerance were successful in half of the patients. Thorwarth et al.56 investigated the effect of dose painting by numbers based on hypoxia information acquired by 18F-FMISO PET. They concluded that this method of dose escalation was more effective than boosting the tumor area an additional time. FMISO PET showed an ability to adequately quantify hypoxia in the tumor area so that dose painting by numbers is achievable leading to increased tumor control. FMISO is not the only hypoxia marker used. Grosu et al.57 evaluated the effect of the use of another hypoxia marker, 18F-fluoroazomycinarabinoside (FAZA), in FAZA PET-CT in RT planning of patients with HNC. It was hypothesized by Grosu et al. that adding FAZA PET to conventional planning CT could add information about tumor diversity to RT planning. That information could be used in dose escalation in hypoxic areas of the tumor. The results showed that FAZA PET can indeed add the before-mentioned information to conventional CT imaging, both in primary tumor and in lymph node metastases, thereby visualizing tumor diversity and making way for accurate dose escalation. On the basis of these promising studies, further prospective studies are needed for better understanding the effect of hypoxia on dose escalation. Potential tumor hypoxia imaging agents include 18F-FMISO and 60Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone). 18F-FMISO is reduced and bound to cell constituents under hypoxic conditions with the level of hypoxia depicted by 18F-FMISO before treatment, correlating with locoregional failure and the absence of hypoxia associated with a low risk of locoregional failure. Treating patients with hypoxic primary tumors with additional cytotoxin resulted in significantly fewer local failures than treating patients with chemotherapy alone, thus showing that hypoxia identification by using biologic imaging can be crucial for prognostication.58
In addition to fluorine-based compounds, the last decade of functional imaging has encountered copper-based agents, because of their well-suited biophysical properties for PET in terms of half-life, emission characteristics, and cell membrane permeability. Although the first Cu isotope examined for tumor hypoxia was 62Cu,59 currently the two most commonly investigated copper-based radiotracers are 60Cu-ATSM (t1/2 = 23.7 minutes) and 64Cu-ATSM (t1/2= 12.7 hours) (diacetyl-2,3 bis(N(4)-methyl-3-thiosemicarbazonato) ligand). With high cell membrane permeability and low redox potential which confers stability in normal tissue, Cu-ligands have proven to exhibit high selectivity for hypoxic cells in both in vitro and in vivo tumor models.60 64Cu-ATSM presented a threefold higher retention in cells with hypoxia as compared to normally oxygenated cells. Some definite advantages of the copper compounds over the commonly used 18F-FMISO for imaging oxygenation status are (1) higher uptake (Cu-ATSM demonstrated up to 90% better uptake in certain cell lines than FMISO); (2) better hypoxia-selectivity of Cu-ATSM, as FMISO indicates hypoxia at lower pO2 values than Cu-ATSM, meaning that good FMISO retention occurs only in areas with pO2 < 2 to 3 mm Hg, whereas Cu-ATSM is taken up also by cells with pO2 > 3 mm Hg; (3) more rapid washout from normally oxygenated tissues. A small study enrolling 12 advanced HNC patients investigated the prognostic effect of 60Cu-ATSM and its role in treatment guidance.61,62 They showed that patients with tumor to muscle ratio (T/M) larger than 4 after 60Cu-ATSM uptake had poorer prognosis compared to those with smaller T/M. There is a need for larger trials to confirm the advantage of copper ligands in functional imaging over the already established radiotracers.63
External beam radiation therapy (EBRT) can be offered to patients with localized disease as radical treatment, alternative to radical prostatectomy, or after surgery as adjuvant or salvage therapy.64–74 The clinical implementation of three-dimensional conformal radiotherapy (3DCRT), IMRT, and IGRT techniques has allowed clinicians to perform a dose escalation with better positioning control and reduced toxicity.75,76
In prostate cancer patients, the volumes of treatment are related to the intent. In the radical setting, prostate gland, and seminal vesicles when indicated, is defined as CTV. In the postoperative setting, the prostatic bed represents the CTV, encompassing anatomic regions at high risk of local relapse, according to the performed prostatectomy.77,78 Recent trials suggested the role of precautional pelvic lymphatic irradiation in prostate cancer patient candidate to EBRT.79 However, the irradiation of draining pelvic lymph nodes remains an object of debate and it is prescribed only when the risk of extraprostatic disease is significantly high.
The installation of CT scan as simulator in daily practice of radiation oncology departments has modified the way to identify target volumes, from 2D to 3D customized targets. CT accuracy of pelvic lymph node metastases, based on lymph node enlargement, is, however, low; nodal size and metastatic involvement are poorly correlated.80,81 Thus, CT simulation images are not useful for complete staging of pelvic extension of disease.
Molecular imaging has become fundamental for tumor staging, for biologic definition, and for delineation of target volumes in radiation oncology. PET and hybrid PET-CT modalities thus are also of increasing interest for radiation oncologists in prostate cancer. In prostate cancer, however, 18F-FDG PET has shown to be of limited value (Fig. 29.5), because of the reduced rate of glycolysis present in prostate cancer cells and the relatively slow growing characteristics.82 Another reason is related to the increased renal excretion and 18F-FDG accumulation in the bladder, which determines a reduced visibility of the pelvic structures, especially lymph nodes.83,84 Moreover, the tracer is not exclusively tumor specific, but also has an increased uptake in benign conditions, such as prostatic hyperplasia or postirradiation inflammation.85–87
The issues mentioned above have driven the efforts to identify new tracers capable to properly investigate prostate cancer. The most widely utilized radiopharmaceutical, applied in clinical setting, is radiolabeled choline (11C-CHO, 18F-fluorocholine).88–91
Another tracer more recently employed in prostate cancer imaging is 11C-acetate.92 This tracer is known to be involved in cell metabolism and lipid synthesis, and since several studies have demonstrated increased fatty acid synthesis in prostate cancer,93,94 acetate-PET is establishing a role in the detection of this tumor. Compared to choline derivatives, radiolabeled acetate has shown similar diagnostic performance, with a potential use in the evaluation of early metabolic changes after anti-androgen therapy.95 In RT planning, 11C-Acetate has recently been utilized for the definition of malignant intraprostatic lesions (IPLs) in prostate cancer for simultaneous integrated boost IMRT (SIBIMRT) capable to give increased doses in high metabolic areas, without increasing treatment toxicity.96
FIGURE 29.5. In this multipanel image are represented the staging FDG PET (left) and Choline PET (right) of the same high-risk prostate cancer patient (PSA, 150 ng/mL). Note the different tracer uptake between the two examinations at the level of primary tumor and lymph node metastases.
11C-CHO and 18F-CHO for Radiotherapy with Salvage Intent in Prostate Cancer
Recurrent disease in clinically organ-confined prostate cancer submitted to radical prostatectomy occurs in 30% to 50% of patients.97,98 In the presence of detectable PSA after surgery or evidence of local recurrence, RTx is to be considered a salvage approach. The use of choline PET scan seems to be promising as restaging procedure for patients who underwent surgery with a rising PSA and appears superior to FDG PET and complementary to conventional imaging.99 One of the principal limits of this technique is a low sensitivity when PSA is lower than 1 ng/mL, that is, when the cancer burden is lowest but most amenable to local therapies, reducing the usefulness of this technique dramatically in studying these kind of patients.100,101 In the light of the suboptimal sensitivity and specificity provided by current imaging modalities, the perfect timing for salvage radiation treatment after biochemical relapse still remains a matter of debate. Nevertheless, salvage RT, with postsurgical PSA values >1 ng/mL is recognized to result in poor outcome and this constitutes a problem, because of the low sensitivity of choline PET.101 Nevertheless, in controversial cases, it is necessary to perform a biopsy of the prostatic bed or a biopsy of the prostate to confirm definitively the presence of a local recurrence under MR or TRUS guidance.102
The correct site of recurrence is crucial for the choice of treatment influencing on individual therapy. Choline PET can be useful both in detecting metastatic disease and in localizing isolated lymph node relapse. A significant PSA rise, after local therapy for prostate cancer, is an insufficient tool to distinguish between isolated local recurrence and occult distant metastases. In the detection of positive lymph node metastases of prostate cancer by choline PET, a sensitivity of 80%, a specificity of 96%, and an accuracy of 93% have been reported, whereas morphologic imaging such as CT and MR correctly detected lymph node metastases in only 7/15 patients (47% sensitivity with a specificity of 98%).86 High PSA levels and advanced pathologic stage are significantly associated with an increased rate of positive 11C-CHO PET-CT findings, and PET could have the potential to detect an isolated nodal recurrence.99,100,103
Accurate staging is critical in postoperative setting as it greatly influences further therapeutic considerations. Schilling et al. performed a histologic verification of 11C-CHO PET-CT nodes in a small population study of 10 patients with biochemical failure after treatment for localized prostate cancer.104 The positive predictive value was 70% and this limited value should lead to a critical interpretation of the results.
Pelvic nodal recurrence occurring after primary therapy is a negative prognostic factor in prostate cancer patients and it could change the treatment planning from salvage to palliative, enabling appropriate selection of patients for salvage local therapy in prostatic bed. Soyka et al. evaluated the clinical impact of 18F-CHO PET-CT in patients with recurrent prostate cancer.105 In 75 of 156 patients (48%) analyzed and submitted to the diagnostic procedure, the treatment plan of RT was changed because of the PET-CT findings. PET-CT with 18F-CHO has shown to have an important impact on the therapeutic strategy in patients with recurrent prostate cancer, increasing the possibility of determining an appropriate treatment.
In a mixed population of 38 patients, composed of primary recurrence and metastatic prostate cancer sites, Jereczek-Fossa et al.106 reported on CyberKnife-based stereotactic RT for 19 isolated lymph node metastases, showing an excellent in-field tumor control and a low toxicity profile. The median follow-up period was 16.9 months and 13 out of 16 patients treated for lymph node metastases (81%) were free of late toxicities; no in-field progression or distant recurrence was documented. In this subset of prostate cancer patients, the optimal combination with androgen deprivation remains a crucial point, without a clear consensus between researchers.
11C-CHO and 18F-CHO for Radical Treatment
Recently, several studies on the use of choline PET as a guiding modality for radical radiation treatment in prostate cancer patients became available.104,107 In comparison with the conventional whole-prostate dose escalation, an integrated boost to the macroscopic malignant lesion has been proposed.108 Using IMRT modalities, treatment planning with 18F-CHO PET-CT has allowed clinicians to perform dose escalation to a macroscopic intraprostatic lesion without significantly increasing toxicity.108 Focusing the dose escalation on the actual tumor is a way to increase tumor control without increasing toxicity. Further clinical results are needed to support the effectiveness of the concept.109 Nevertheless, Choline PET-CT is still not suggested for use in primary prostate cancer because of an important limitation of relatively poor values of sensitivity and specificity for localizing tumor disease in the prostate gland (71.6% and 42.6%, respectively).110 Cost-effectiveness analyses are also needed to evaluate PET choline-tailored treatments.111
The introduction of PET and PET-CT in the routine protocols for the diagnosis and staging of lung cancer has been proved having a high impact on the management of patients.112–114 There are many studies assessing the sensitivity of PET in lung cancer, particularly in non–small-cell lung cancer (NSCLC).115
Surgery is still the treatment of choice for eligible patients, but RT is a key element in the treatment strategy. Its role in the patient’s work-up is well established in NSCLC and is of improving importance in SCLC. A more tailored therapy planning relies on advanced diagnostic procedures and 18F-FDG PET-CT is widely recognized as high performing imaging for lung cancer.116 With regard to RT planning, we can summarize PET-CT applications as follows.
• Evaluation of indeterminate lung lesions
• Staging either for nodal involvement or for distant metastasis
• Detection of recurrent/relapsed disease
We here intend to catch a glimpse of PET-CT applications in lung cancer and give a close look at the state of the art usage of PET-CT in RT planning for lung cancer, pointing out its clinical role. Data for both NSCLC and SCLC have been evaluated separately into two sections.
Non–Small-Cell Lung Cancer
Clinical and pathologic features contribute to staging the tumor which plays a critical role in the management of the patients with NSCLC. Surgery is the best option when applicable, although RT and chemotherapy might be proposed for patient with no surgery eligibility or with the aim of palliation in advanced-stage diseases.117–119
18F-FDG PET and PET-CT specificity and sensitivity have been investigated in several studies, particularly in the evaluation of indeterminate lung lesions where a high sensitivity is reported, ranging from 79%120 to 96%.121Specificity has been reported ranging from 40% to 80%, the specificity being lower than the sensitivity because of the possible false-positive results caused by inflammatory changes (Table 29.1).122–124
Nodal involvement and distant metastasis are crucial to determine whether a patient needs to undergo RT or not, identifying those who can benefit from radical RT and excluding incurable patients that will need different palliative cures. Sensitivity (74% to 85%) and specificity (85% to 92%) for detecting nodal involvement were analyzed in various studies (Table 29.2).125–129 Moreover, the high negative predictive value (90%) in the detection of mediastinal nodes appears to be fundamental in FDG PET-CT scanning. Finally, as PET-CT is a total-body imaging technique, it allows for the detection of distant metastases with a mean sensitivity of 93% and a mean specificity of 96% as reported by the National Institute for Clinical Excellence (NICE),130 data confirmed also by Ung et al.120 Local recurrence is detected with a reported sensitivity of 99% and specificity of 89%.113,122,128
FDG PET IN THE EVALUATION OF INDETERMINATE LUNG LESIONS
PET-CT improves the RT performance and, therefore, its clinical outcome concerning the selection of patients and allowing a more suited treatment for patients eligible for RT. If available, PET-CT should always be used to contribute to definitive RT planning of NSCLC.
Small-Cell Lung Cancer
Small-cell lung cancer (SCLC) is responsive to the treatment with both chemotherapy and RT. These treatment modalities can more effectively prolong survival than local treatment like surgery because the disease is more likely to spread with metastasis than to develop a local invasion pattern. If the tumor is confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes, patients are designated as having limited-stage disease (LD). Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED) and a worse prognosis. Patients with distant metastases are always considered to have ED.131,132
Schumacher et al.24,133 confirmed that PET-CT clinical role overwhelms its mere diagnostic importance as the differentiation between LD and ED is fundamental not only for staging purposes but also for choosing therapy strategies. Sensitivity and specificity reported for the distinction of LD and ED range between 89% to 100% and 78% to 100%, respectively (Table 29.3).133,134 FDG PET-CT appears to be more accurate than conventional imaging with CT in depicting the extrathoracic nodal metastasis and initial bone marrow involvement.133,134 Trials with chemotherapy and RT have shown increased survival in patients with LD. PET-CT can be used in SCLC patients mainly to upstage from LD to ED or vice versa and possibly to extend the tumor target volume for RT to additionally detected nodes,135 but there is still a limited experience when compared to NSCLC.
FDG PET IN MEDIASTINAL LYMPH NODE STAGING OF NON–SMALL-CELL LUNG CANCER
DIAGNOSTIC PERFORMANCE OF FDG PET IN SMALL-CELL LUNG CANCER
RT Planning in Lung Carcinoma
Integrating PET-CT in RT planning needs rigorous procedures and a chain of quality controls to ensure the correct patient positioning, thereby avoiding discrepancies between the “imaging position” and the “treatment position.” This is made possible; thanks to the positioning tools like immobilization devices fixed on a firm flat couch top and laser beams. A dedicated PET-CT is required when only a diagnostic PET-CT is available.136
The definition of the target volume can be visually or semiautomatically assessed. The GTV definition can benefit from SUV-based contouring and threshold techniques to distinguish the lesion from the background.137–139
In recent years, the potential for SBRT to target small tumor volumes in this setting has become a topic of active investigation. Current experience supports the curative potential for tumors under 5 to 6 cm.140 Few studies have evaluated the relationship of PET imaging with SBRT in the liver. A study by Casamassima et al.141 included 48 patients (15 primary, 33 metastases) treated for 69 liver lesions with SBRT. PET images were available in 22 patients prior to treatment. Response was evaluated 60 days after treatment by CT, carcinoembryonic antigen (CEA) levels (for those with colonic metastases) and PET (n = 9). At median follow-up of 8.2 months (range: 2 to 24), 28 patients were still alive, 7 died from progressive disease in liver, 7 from progressive disease outside the liver and 6 died of other causes. In the nine patients with PET imaging, one demonstrated resolution of uptake, in six there was visually apparent decrease in uptake (SUV unavailable) and for the remaining two, SUV was 4.5 and 8. Although tumor response was difficult to evaluate by CT because the irradiated area appeared hypodense, the authors argued that both CT and blood tumor markers may be more reliable than PET in the evaluation of tumor response owing to the uptake of reactive tissue. So far one study retrospectively reviewed the value of FDG PET-CT for RT planning in 19 patients with colorectal liver metastasis treated with HDR brachytherapy for 38 lesions in 25 sessions.142 Adding the information from FDG PET to the planning CT resulted in a change in the CTV in 84% of all sessions. An increase was observed in 15 sessions, although in 6 sessions the CTV decreased. The median PET-CT CTV was significantly larger than the CT CTV with a median increase of 24.5% (p = 0.022). The authors observed a significantly larger rate of early local progression in those patients with incomplete PET-CT CTV coverage. They, therefore, concluded that PET is particularly informative for pretreated lesions, when CT is inconclusive. This is in contrast to the observations by Akhurst et al.143 who found that preoperative chemotherapy reduces the activity of the glycolytic enzyme hexokinase which resulted in a reduction in sensitivity of standard FDG PET for colorectal metastasis. In any case, FDG PET holds promise when considering irradiating liver metastasis up to a high dose, but warrants further research.
In the treatment of esophageal cancer, RT is commonly used in combination with chemotherapy as neoadjuvant treatment prior to surgery or as definitive approach in patients not fitted for extensive surgery. Currently, modern RT includes TVD based on planning CT scan. The value of FDG PET to determine the regional extent of the disease has been investigated in a few studies. Shimizu et al.144 investigated FDG PET-CT and EUS in 20 patients who received radical surgery for SCC of the esophagus. They found that the detection rate of subclinical lymph node metastasis did not improve with the addition of PET.
18F-FDG PET/CT shows a sensitivity of 94% and a specificity of 90% for primary cancer, superior to that of CT (84% and 75%, respectively),145,146 but has a suboptimal performance for locoregional lymph nodes (49% to 76%).147,148 The sensitivity, however, increases significantly (up to 95%) when looking for distant metastases, such as hepatic or bony lesions.149 Despite these good prerogatives, FDG PET has been employed only in a few cases for RT planning.150–153
Other tracers have been investigated. 18F-fluorothymidine (FLT) is an example of an amino acid tracer that is now assessed by several groups. In the first pilot study,154 FLT focal uptake was detected only in malignant lesions, suggesting that FLT PET might have an additional value over FDG PET for differentiating cancer from benign pancreatic lesions. More recently, in a pool of 46 patients with pancreatic tumors staged and evaluated before surgical resection, FDG PET showed a higher sensitivity, but lower specificity than FLT PET.155 Moreover, mean SUVmax for FDG PET was significantly higher than that of FLT PET (3 versus 7.9, respectively; p < 0.001). At the moment, the role of FLT PET in pancreatic cancer seems to be insufficiently assessed and still limited, when compared to FDG.150
Preoperative chemoradiation is the standard treatment for locally advanced rectal cancer.156 The CTV includes the primary tumor, regional lymph nodes, and pelvic areas at risk for subclinical disease.157 Accurate dose delivery and the possibility of modulating the dose prescription with IMRT pave the way for the use of molecular imaging as a promising tool for selecting specific areas in a tumor that may be more radiation resistant. The usefulness of PET with 18F-FDG has been investigated for the initial staging of colorectal cancer.158–160 All of those studies suggested that preoperative PET is useful for the diagnosis of the primary tumor but is of limited value for detecting metastases to the regional lymph nodes (Fig. 29.6). One study has evaluated the accuracy of TVD based on the PET data from an integrated PET-CT system with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) for standardized target-volume delineation. Buijsen et al.161 have investigated 42 patients undergoing FDG PET before RT planning. When using an automatic contouring, authors detected an increased inter-observer agreement on tumor delineation, associated with an additional improvement in GVT definition. In fact, up to 29% of the cases, PET images determined an extension of CTV outside CT/MR treatment planning. However, these findings must be interpreted with great caution. The limited accuracy of FDG PET in detecting microscopic lymph node invasion makes it unsuitable for the automatic definition of a CTV or PTV.162 Reducing the inter-observer variability by means of functional image-guided radiation treatment planning still remains a felt and debated concern in the radiation oncology community. This issue has been addressed by Patel et al.163 who compared the nodal and primary tumor GTV contour for a hypothetical boost volume on conventional CT alone and on FDG PET-CT and FLT PET-CT in six rectal cancer patients. They found that the boost volumes based on combined PET-CT resulted in a lower inter-observer variability compared with CT alone, particularly for nodal disease. In conclusion, even if PET can provide additional functional information, which can be worthwhile in the delineation of the GTV in rectal cancer, its usefulness in the treatment of rectal cancer is still questionable and needs to be evaluated in prospective trials. Furthermore, an accurate definition of the margins around the CTV is mandatory when delivering high doses onto a highly deformable and mobile organ such as the rectum.
FIGURE 29.6. FDG PET for radiotherapy planning of a patient with colorectal cancer. (A)] Local recurrence in the pelvic structures involving also sacral bone. (B and C): Loco-regional lymph node metastases, omolateral (C) and contralateral (B) to the relapse. (D): Distant liver metastasis.
Despite the fact that there is still limited evidence of the role of FDG PET in RT planning of anal cancer,150,164–166 data so far available demonstrate a relevant impact of the method on delineation volumes. First, FDG PET helps in proper staging of the disease (up to 23% change in tumor stage), and second, it determines a better delineation of the target volumes.166,167 Moreover, Mai et al.165 have investigated the impact of FDG PET findings on treatment decisions and discovered that the reduction of the irradiation dose to PET-negative inguinal lymph nodes does not affect disease failure.
CT and MR provide an accurate evaluation of the primary tumor size, depth of stromal invasion, stage of disease, and detection of lymph nodes or distant metastasis. However, they are not sufficiently accurate for the adequate evaluation of nodal spread.168
PET-CT with 18F-FDG seems to have an important role in staging and restaging of gynecologic malignancies, especially regarding lymph node involvement or recurrent tumor because of the simultaneous functional and anatomical information.169,170 There is also a large field of PET-CT application in response monitoring and RT planning. 18F-FDG PET-CT can be used for “dose painting,” with the intent to deliver higher dose toward the more sensitive tumor areas.171 Although there are several studies that evaluate the role of FDG PET in primary tumor staging, neither PET nor CT are useful methods for detecting parametrial disease and both are limited in detecting the primary tumor, especially in early stage disease.172
FIGURE 29.7. Evidence of FDG-positive lymph node in common iliac region.
The presence of lymph node involvement is one of the strongest prognostic factors in patients affected by cervical cancer (Fig. 29.7). When para-aortic lymph node metastases are detected, patients benefit from pelvic RT combined with chemotherapy protocols.173 The evaluation of lymph node metastasis with MR and CT is based on lymph node dimensions and usually could detect abnormalities greater than 1 cm.
The accuracy of FDG PET-CT in the evaluation of pelvic lymph node status in early stage cervical cancer patients is demonstrated to be low and to be unfit for replacing surgical exploration.174
In patients with advanced disease and negative conventional imaging, PET-CT specificity and accuracy for detecting para-aortic lymph node metastasis were particularly high (84% and 75%) and there was a treatment modification in 25% of patients based on PET results.175 In a recent prospective cohort study that included 560 patients with newly diagnosed cervical cancer, the extent of lymph node involvement on PET seems to stratify patients into distinct outcome groups, suggesting that lymph node staging with FDG PET influences the prognosis of patients. The frequency and the pattern of cervical cancer lymph node metastasis on FDG PET are correlated to the FIGO stage and parallels historical surgical data.176
The FDG PET-CT detection of supraclavicular lymph node metastasis is a predictor of a very poor patient’s prognosis and can obviate unnecessary treatments since even if aggressive therapy can be useful to control pelvic disease all patients tend to develop distant metastasis in time. Tran et al.177 reported that the frequency of PET-detected supraclavicular metastasis was around 15% for patients with clinical stage IIIb disease and about 40% for those with abnormal FDG uptake in para-aortic nodes, so FDG PET-CT seemed to be an appropriate method for evaluating the supraclavicular lymph nodes in patients with invasive cervical carcinoma.177
Concomitant chemo-radiotherapy (CT/RT) represents the standard treatment in patients with LACC based on the results of five randomized phase III studies that demonstrated an advantage in terms of disease-free survival (DFS) and overall survival (OS) for CT/RT compared to exclusive RT.178,179 Details of the EBRT fields used in the management of cervical cancer are well described by other authors.173,178–190 In the setting of pelvic nodal or parametrial disease, additional dose may be delivered by anterior posterior:posterior anterior (AP:PA) fields using a midline block, 3DCRT or IMRT. The cumulative dose delivered by EBRT and brachytherapy must be carefully integrated during treatment planning to avoid significant overexposure to midline structures, particularly the ureters and rectum.
3DCRT or IMRT may also be used for a nodal boost in the para-aortic region to minimize the dose to small bowel.191,192 Normal-tissue constraints and dose reporting for the small bowel and kidneys are described in the Quantitative Analyses of Normal-Tissue Effects in the Clinic review.193,194 Although IMRT is becoming more widely available, the use of IMRT in the definitive treatment of cervical cancer has not yet been validated, given the concerns about target definition, inter- and intrafraction motion, and tumor regression during treatment.195,196
Narayan et al.197 assessed whether PET or MR could avoid surgical staging in 27 patients with locally advanced cervical carcinoma planned for RT. The authors concluded that PET had superior sensitivity to MR but still missed small-volume disease and they recommended para-aortic lymph node dissection in all patients with positive pelvic lymph nodes on PET. Conversely, the 98% positive predictive value of PET-CT was high enough to avoid pathologic confirmation and led to extended field RT.
PET-CT with FDG represents a useful tool to better select candidates for concomitant chemoradiation. Loft et al.198 prospectively assessed the diagnostic value of PET-CT in 120 patients with cervical cancer stage P1B. Sensitivity and specificity of PET-CT for pelvic node diagnosis were 75% and 96%, respectively. Regarding para-aortal nodal disease, sensitivity and specificity were 100% and 94%, respectively. This confirms that the use of whole-body FDG PET-CT scanning for newly diagnosed cervical cancer with FIGO stage P1B2 has a high sensitivity and specificity and allows a more adapted therapeutic strategy.
FIGURE 29.8. Evidence of residual tumor with faint FDG uptake after brachytherapy.
A few studies have assessed the use of PET for 3D brachytherapy. Malyapa et al.199 compared 2D treatment planning orthogonal radiography-based brachytherapy with a 3D treatment planning based on 18F-FDG PET in 11 patients with cervical cancer. The patients underwent two PET scans: First one to visualize the tumor and second one with the FDG placed inside the tandem and ovoid applicators to visualize the author’s treatment source positions for 3D treatment planning. They concluded that this technique was feasible and accurate relative to 2D treatment planning (Fig. 29.8). Further studies are necessary to strengthen the evidence of PET-CT impact on patient life quality improvement and overall survival.
THE INCIDENCE OF BRAIN TUMORSa
According to the current World Health Organization (WHO) classification of brain tumors, gliomas are assigned grades I to IV, as shown in Table 29.4. These tumors are usually surrounded by extensive edema and, in 5% to 10% of glioblastomas, the disease is already multifocal at the time of diagnosis.200 Consequently, gliomas cannot be totally removed by any form of local treatment, surgery included (Table 29.5). Cytotoxic therapy may fail too, because migrating cells are less likely than non-migrating cells to be in the chemosensitive cell-division phase.
The treatment of gliomas is highly individualized at present, based on the histologic diagnosis and other factors, and will be even more so in the future. It is now well established that the prognosis of a patient with glioma depends, in general, on the histologic classification of the tumor, the tumor grade, the patient’s Karnofsky performance score, and neurologic deficits as well as the patient’s age. New molecular markers, such as loss of heterozygosity (LOH) of chromosome 1p/19q, methylation of the methylguanine methyltransferase (MGMT) promoter, and mutations of isocitrate dehydrogenase-1 (IDH-1), now enable more accurate prognosis (Table 29.6).201–207
PRIMARY TREATMENT OF DIFFERENT TYPES OF GLIOMAa
FUNCTION AND SIGNIFICANCE OF THE MAIN MOLECULAR MARKERS OF GLIOMA
No advantage in terms of overall survival has been found for immediate postoperative RT of grade II gliomas as compared to follow-up observation after resection, despite the demonstrated advantage with respect to the time to tumor progression.208 Thus, once the diagnosis of grade II glioma has been histologically confirmed, it is best to adopt a wait-and-see strategy. This is particularly true for patients under age 40, whose prognosis is better than that of others by virtue of their age.209
On the other hand, the standard treatment for tumor progression after initial resection of low-grade gliomas (LGGs) is fractionated low-dose RT to 45 or 50.4 Gy, possibly preceded by resection of the recurrent tumor.210 No benefit has yet been documented for chemotherapy instead of, or in addition to, RT in the treatment of diffuse grade II astrocytoma.
Newly diagnosed gliomas of WHO grade III include anaplastic astrocytoma, oligoastrocytoma, and oligodendroglioma. Oligodendroglial tumors also often have areas of calcification and mild perifocal edema. There is no substitute for histologic confirmation of the diagnosis, because grade III tumors cannot be securely differentiated from grade II tumors on radiologic grounds alone, nor can imaging studies conclusively show the presence or absence of an oligodendroglial component. As much of the tumor as possible should be removed by open, microsurgical resection, if the location of the tumor permits.205 After resection, a combination of chemotherapy and RT has no advantage over either of these modalities alone with respect to overall survival,211 nor is there any difference between chemotherapy alone and RT alone (multi-center trial of the Neuro-Oncology Working Group of the German Cancer Society, NOA-04 Study).205 The median overall survival time in the NOA-04 Study was 72.1 months after RT and 82.6 months after chemotherapy; the difference was not statistically significant.
The RT of glioblastoma involves the delivery of an overall dose of 60 Gray (in fractions of 1.8 to 2 Gy each) focused on the tumor target volume, with a marked dose fall-off in the surrounding brain tissue. IMRT is a recent advance in technique that allows modification of linear accelerator output, which improves target coverage and allows for reduction of radiation dose to radiation-sensitive structures. Use of abbreviated course of radiation (total: 40 to 50 Gy) in older patients has been shown to be efficacious.212
Impact of PET Imaging in Radiation Therapy Planning in Brain Tumors
Radiation therapy is so far a milestone in brain tumor treatment, either at first presentation or after relapse and surgical removal. Especially in a postoperative setting, RT is known to increase overall survival in high-grade gliomas, namely glioblastoma multiforme (GBM) and anaplastic astrocytoma.213–216 As for other districts, RT planning requires a proper definition of treatment volumes, including GTV, which defines gross tumor mass extension. However, because of the major functional relevance of brain structures, the definition of these volumes for RT planning necessitates additional attention and a high accuracy of imaging techniques.
Up to now, definition of GTV is mainly based on CT and MR. Both these imaging modalities accurately show primary tumor and surrounding areas, thanks to the contrast enhancement and hyperintensity on T2- or flair-MR,217but these findings are not always tumor specific. CT and MR in fact can give outstanding information on tumor localization and dimension but cannot differentiate residual tumor from fibrotic tissue and posttreatment alterations. The reason stands on the direct dependence of CT and MR imaging on the discontinuity of blood–brain barrier (BBB) to characterize pathologic tissue. But these same findings can be present also in edema, postradiation injuries, regenerative tissue, etc.213,218–220 For this reason, functional imaging with PET has gained an increasing role in radiation therapy planning also for brain tumors (Fig. 29.9).
The first PET radiopharmaceutical utilized for imaging of brain tumors was 18F-FDG.221 The tracer is the principal oncologic compound worldwide and has also been investigated in central nervous system malignancies.222,22318F-FDG uptake is generally high in high-grade tumors and brain metastasis, demonstrating an important prognostic value in attrition.224 However, recent studies have demonstrated some diagnostic limitations of 18F-FDG PET. Because of the high rate of physiologic glucose metabolism in normal brain tissue, the detectability of tumors with only modest increase in glucose metabolism, such as low-grade tumors and in some cases of recurrent high-grade tumors, is difficult. 18F-FDG uptake in low-grade tumors is usually similar to that in normal white matter, and uptake in high-grade tumors can be less than or similar to that in normal gray matter, thus decreasing the sensitivity of lesion detection.225
The number of radiolabeled compounds available for PET imaging is relatively high (Table 29.7)52,221,230–236 and principally includes amino acids (i.e., 11C-MET, 18F-FET, etc.), which remain the tracers more widely employed and investigated in brain tumors (Fig. 29.10).217,230,231
FIGURE 29.9. Herein are represented the possible clinical target volumes (CTV) according to the percentage of overlap between gross tumor volumes (GTV) based on MR and PET imaging.
11C-MET is undoubtedly the principal PET tracer for brain neoplasms,237 concerning either initial diagnosis and image-guided biopsy,238–240 staging and restaging tumor recurrence,241–245 prognosis246 or RT planning.217,247Overall, the method has demonstrated a good performance in diagnosing brain tumors (sensitivity and specificity of 87% to 100% and 75% to 100%, respectively),237–240 as well as in differentiating recurrence from radiation necrosis or other postoperative alterations (sensitivity and specificity of 78% to 100% and 60% to 100%, respectively).237,243–245
The main limitation, however, of 11C-MET is the short half-life of the radionuclide carbon-11 (t1/2 ∼ 20 minutes), thus the absolute necessity of an on-site cyclotron for its production. For this reason, another amino acid tracer is also being employed in imaging brain tumors, this is the case of fluoroethyltyrosine (FET), labeled with fluoride-18 (t1/2 ∼ 110 minutes). The diagnostic accuracy of this other tracer has so far resulted equal to that of 11C-MET, with a high sensitivity and specificity up to 80% to 90% (Figs. 29.11, 29.12).230,248
PRINCIPAL PET TRACERS UTILIZED FOR IMAGING PRIMARY AND SECONDARY BRAIN TUMORS
FIGURE 29.10. Axial images of fused FDG PET-CT (upper panel), MET PET-CT (middle panel) and corresponding low-dose CT (lower panel) of the same patient. Note the different patterns of uptake in between a glucomimetic tracer, such as 18F-fluorodeoxyglucose (dashed arrow ). and an amino acidic tracer, such as 11C-Methionine (straight arrow ). Both scans demonstrated increased uptake in the same region, although MET PET had a higher and more distinguishable uptake than FDG PET. The lesion, surrounded by a vast hypointense area in the left peritrigonal region, is also well visualized on LD CT (arrowhead ).
Amino Acid Tracers
One of the first evidences of implemented value of 11C-MET in brain tumors was reported on brachytherapy in gliomas.249 Out of the 46 patients investigated, disease extent with MET PET resulted superior in 67% of the cases, compared to that determined by CT/MR, concluding that the method could improve tumor delineation and provide additional information on therapeutic effects.86,249 Findings were subsequently confirmed by Nuutinen et al.250 in LGGs, where MET PET improved GTV delineation in 63% of the patients: 27% of cases in outlining MR-GTV and 46% in giving complementary information.
Also in postoperatively imaged high-grade gliomas, Grosu et al.251 report that 11C-MET uptake and MR contrast enhancement could correspond in only 13% of patients (n = 39), with a mean volume of 13 mL (33%) of the tumor showing no contrast enhancement on MR. The same authors had previously demonstrated that in 79% of the patient, the region of MET uptake was larger than that of contrast enhancement on MR (up to 45 mm beyond), whereas in 74% the MR-contrasted area extended beyond the MET.252
Also in a pool of 16 patients with malignant glioma, candidates for Carbon Ion radiotherapy, Mahasittiwat et al.213 could detect a mean extended volume (EV) of MET PET over MR CTV of 0.6 and 2.2 mL, which significantly correlated with patient survival: Greater survival rate (p = 0.0069), regional control (p = 0.0047), and distant control time (p = 0.0267) for those having a negative EV, compared to those with a positive EV.
One of the reasons for treatment failure in RT is the presence of low oxygen levels in the tumor tissue. The brain tumor known for hypoxic areas is glioblastoma. This type of tumor presents with a variable pattern of tissue neovascularization, associated with oxygen depletion and promotion of new aberrant tumor cell proliferation.52,253,254 This is the reason why new PET tracers have been applied for the characterization of tumor oxygenation, starting with 18F-fluoromisonidazole (FMISO),255–257 a nitromidazole derivative.255,258 In the presence of oxygen depletion, nitromidazoles are metabolized by the enzyme nitroreductase, thus can be covalently bound to intracellular macromolecules and be entrapped within the cells. This is the mechanism used in the case of FMISO, which is collected in the tumor cells proportionate to the amount of hypoxia.253,258
In glioma, the binding potential of FMISO has demonstrated a fair correlation with tumor grade,259 with glioblastoma showing a high tracer uptake in all cases and LGGs having no FMISO uptake.259,260
Moreover, according to recent findings,257,260 viable hypoxic tissue assessed by FMISO PET seems to occupy regions straddling the outer edge of the T1-weighted Gd-enhanced areas on MR, suggesting as underlying cause the driving of peripheral infiltration by tumor hypoxia.256 On a molecular level, the explanation for this characteristic appears to be related to the expression level of HIF-1, a transcriptional factor playing a crucial role in promoting cell survival, tumor invasiveness, and aggressiveness.260,261 More specifically, some studies have demonstrated that HIF-1α localizes in cells around necrosis and tumor cells infiltrating the surrounding brain close to tumor margins.259,262
When comparing MET PET and FMISO PET, it seems likely that the two tracers give complementary information, helping in a more efficient tumor delineation and better RT planning. These findings appear to open the way to the possibility of dose-painting treatment planning, based on the hypoxic target volumes derived from FMISO PET. This is the reason why various clinical trials are being conducted on hypoxia imaging of brain tumors (Table 29.8). Further data and dedicated investigation are, however, necessary to properly define the role of hypoxia imaging in RT planning of brain tumors.
Other PET Tracers
Imaging gliomas are not only a prerogative of 11C-MET or 18F-FET, because other radiopharmaceuticals, usually employed for other malignancies or body districts, have been applied in brain tumors (Table 29.7). The tracer showing more uptake similarities to the abovementioned amino acid tracers is 18F-fluorodihydroxyphenylalanine (18F-DOPA). First developed for PET imaging of neurodegenerative and movement disorders,263 the radiopharmaceutical is nowadays largely employed for imaging neuroendocrine tumors (NET).264 As an analog of the amino acid phenylalanine, 18F-DOPA is actively taken up via the large amino acid transporter (LAT) and subsequently decarboxylated within the cell into dopamine, thanks to the aromatic acid decarboxylase (AADC).265 This mechanism is increased also in tumors other than NET, including primary brain tumors,266 and has resulted helpful in detecting or defining newly diagnosed gliomas (sensibility and specificity of 85% and 89%, respectively).232,267 The tracer uptake was reported to correlate to histologic findings and tumor grade, giving additional prognostic information, compared to the other amino acid tracers.232
FIGURE 29.11. In this multipanel image are shown MET PET and RM of a patient with recurrent pilocytic astrocytoma of the right thalamus: (A) axial PET images for radiotherapy planning; (B)corresponding T1-w contrast enhanced MR images.
Also 11C-CHO has been investigated in imaging brain tumors.233 As an essential amine, it enters several metabolic pathways, but the most relevant one for cancer imaging is its incorporation into cell membranes as phosphatidylcholine.268 The increase of choline levels in brain tumors is a well-known process on which relies MR spectroscopy269 and more recently, also PET imaging. Available data233,270–272 show a good diagnostic accuracy for 11C-CHO in different gliomas, both low-grade and high-grade, and suggest a superior performance of this tracer in defining target volumes before RT planning, with a GTV change in 80% and 14.3%, respectively for grade II and III gliomas, compared to MR volumes.233
FIGURE 29.12. Same patient as in Figure 29.11, but herein are shown the radiotherapy planning (A) and the corresponding MET PET, green line, and CT contouring, red line (B).
ONGOING TRIALS ON FMISO PET IMAGING IN RADIOTHERAPY PLANNING IN BRAIN TUMORS
Developed by Shields et al.273 in the 1990s, 18F-FLT is normally utilized for imaging tissue proliferation, and more precisely thymidine kinase 1 (TK1) activity, a cytosolic enzyme significantly overexpressed in proliferating tumor cells.234,274 Several neoplasia have been imaged with 18F-FLT PET and more recently also brain tumors.234,275–277 Findings seem to indicate some interesting potential for 18F-FLT in differentiating low-grade from high-grade gliomas, directly related to Ki67 expression,275 and in giving complementary information on the extent of disease. This latter point can be of great importance in RT planning of brain tumors.
Another process having an important role in the growing and spreading of brain tumor is angiogenesis. The phenomenon has been extensively investigated and can be indirectly visualized by means of integrin αvβ3 analogs, such as arginine-glycine-aspartic acid (RGD)-peptides.235 Integrin αvβ3 is an important receptor for cell adhesion and is overexpressed in activated endothelial cells and gliomas.278,279 Its radiolabeled antagonists are currently employed for imaging brain-tumor–associated angiogenesis in high-grade gliomas.217
At last, we want to mention another category of tracers, showing an unusual application in brain tumors: This is the case of gallium-68 labeled somatostatin analogs.217,236,280,281 These tracers are typically applied for imaging somatostatin receptor expression in NET,282 but have demonstrated a high accuracy in defining meningiomas and in delineating tumor margins with respect to normal tissue.217
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