PET/CT in radiation oncology

The progressive integration of positron emission tomography/computed tomography (PET/CT) imaging in radiation therapy has its rationale in the biological intertumoral and intratumoral heterogeneity of malignant lesions that require the individual adjustment of radiation dose to obtain an effective local tumor control in cancer patients. PET/CT provides information on the biological features of tumor lesions such as metabolism, hypoxia, and proliferation that can identify radioresistant regions and be exploited to optimize treatment plans. Here, we provide an overview of the basic principles of PET-based target volume selection and definition using ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) and then we focus on the emerging strategies of dose painting and adaptive radiotherapy using different tracers. Previous studies provided consistent evidence that integration of ¹⁸F-FDG PET/CT in radiotherapy planning improves delineation of target volumes and reduces the uncertainties and variabilities of anatomical delineation of tumor sites. PET-based dose painting and adaptive radiotherapy are feasible strategies although their clinical implementation is highly demanding and requires strong technical, computational, and logistic efforts. Further prospective clinical trials evaluating local tumor control, survival, and toxicity of these emerging strategies will promote the full integration of PET/CT in radiation oncology.     

PET and MRI based RT treatment planning: Handling uncertainties

Imaging provides the basis for radiotherapy. Multi-modality images are used for target delineation (primary tumor and nodes, boost volume) and organs at risk, treatment guidance, outcome prediction, and treatment assessment. Next to anatomical information, more and more functional imaging is being used. The current paper provides a brief overview of the different applications of imaging techniques used in the radiotherapy process, focusing on uncertainties and QA. The paper mainly focuses on PET and MRI, but also provides a short discussion on DCE-CT. A close collaboration between radiology, nuclear medicine and radiotherapy departments provides the key to improve the quality of radiotherapy. Jointly developed imaging protocols (RT position setup, immobilization tools, lasers, flat table…), and QA programs are mandatory. For PET, suitable windowing in consultation with a Nuclear Medicine Physician is crucial (differentiation benign/malignant lesions, artifacts…). A basic knowledge of MRI sequences is required, in such a way that geometrical distortions are easily recognized by all members the RT and RT physics team. If this is not the case, then the radiologist should be introduced systematically in the delineation process and multidisciplinary meetings need to be organized regularly. For each image modality and each image registration process, the associated uncertainties need to be determined and integrated in the PTV margin. When using functional information for dose painting, response assessment or outcome prediction, collaboration between the different departments is even more important. Limitations of imaging based biomarkers (specificity, sensitivity) should be known.     

Implementation of hypoxia imaging into treatment planning and delivery

Purpose

To review the current status of implementation of functional hypoxia imaging in radiotherapy (RT) planning and treatment delivery.

Methods

Before biological imaging techniques such as positron emission tomography (PET) or magnetic resonance (MR) can be used for individual RT adaptation, three main requirements have to be fulfilled. First, tissue parameters have to be derived from the imaging data that correlate with individual therapy outcome. Then, the spatial and temporal stability of hypoxia PET images needs to be established. Finally, the dose painting (DP) concepts have to be practically feasible to be used as a basis for clinical trials.

Results

A number of recent clinical studies could show the correlation of hypoxia PET imaging with different tracers and RT outcome. Most of the studies revealed a correlation between mean or maximum values and parameters assessed from the PET avid volume and treatment success, only few investigations used quantitative imaging. Multiparametric imaging seems to be very valuable. Recently, the spatial and temporal stability of hypoxia PET attracted attention. Temporal changes in the distribution of functional tumour properties were reported. Furthermore, technical feasibility of DP by contours (DPC) as well as DP by numbers (DPBN) was shown by several investigators. The challenge is now to design clinical studies in order to prove the impact of DP treatments on individual therapy success.

Conclusion

A patient-specific adaptation of RT based on functional hypoxia imaging with PET is possible and promising. Conceptual feasibility could be shown for DPBN whereas to date, only DPC seems to be plausible and feasible in a clinical context.     

Biological imaging in radiation oncology

The goal of this study was to discuss the value of integrating biological imaging (PET, SPECT, MRS etc.) in radiation treatment planning and monitoring. Studies in patients with brain tumors have shown that, compared to CT and MRI alone, the image fusion of CT/MRI and amino acid SPECT or PET allows a more correct delineation of gross tumor volume (GTV) and planning target volume (PTV). For FDG-PET comparable results with different techniques are reported in the literature also for bronchial carcinoma, ear-nose-and-throat tumors, and cervical carcinoma, or, in the case of MRS, for prostate cancer. Imaging of hypoxia, cell proliferation, apoptosis, tumor angiogenesis, and gene expression leads to the identification of differently aggressive areas of a biologically inhomogeneous tumor mass that can be individually and more appropriately targeted using innovative IMRT. Thus, a biological, inhomogeneous dose distribution can be generated, the so-called dose painting. In addition, the biological imaging can play a significant role in the evaluation of the therapy response after radiochemotherapy. Clinical studies in ear-nose-and-throat tumors, bronchial carcinoma, esophagus carcinoma, and cervical carcinoma suggest that the sensitivity and specificity of FDG-PET for the therapy response are higher compared to anatomical imaging (CT and MRI). Clinical and experimental studies are required to define the real impact of these investigations in radiation treatment planning, and especially in the evaluation of therapy response.     

Clinical use of positron emission tomography for radiotherapy planning – Medical physics considerations

PET/CT imaging plays an increasing role in radiotherapy treatment planning. The aim of this article was to identify the major use cases and technical as well as medical physics challenges during integration of these data into treatment planning. Dedicated aspects, such as (i) PET/CT-based radiotherapy simulation, (ii) PET-based target volume delineation, (iii) functional avoidance to optimized organ-at-risk sparing and (iv) functionally adapted individualized radiotherapy are discussed in this article. Furthermore, medical physics aspects to be taken into account are summarized and presented in form of check-lists.     

Apport de l’imagerie fonctionnelle dans la radiothérapie des cancers des voies aérodigestives supérieures : vers l’adaptation à la biologie ?

Radiotherapy based on functional imaging consists to deliver a heterogeneity dose based on biological proprieties. This approach is termed biologically conformal radiotherapy or dose painting with biological target volume inside the gross tumor volume. Diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced MRI can also be used to define a specific biological target volume. Three main tracers are used: (¹⁸F)-fluorodeoxyglucose to target the hypermetabolism, (¹⁸F)-fluoromizonidazole and (¹⁸F)- fluoroazomycin arabinoside to target areas of hypoxia. In this review, we give a practical approach to achieving a treatment-guided radiotherapy molecular and the main issues raised by this imaging technique. Despite the provision of all the technological tools to the radiotherapist, this new therapeutic approach is still evaluated in clinical studies to demonstrate a real clinical benefit compared to radiotherapy based on anatomic imaging.     

Rôle potentiel de la TEP-FDG pour la définition du volume tumoral macroscopique (GTV) des cancers des voies aérodigestives supérieures et du poumon

The recent progresses performed in imaging, computational and technological fields bring new opportunities to achieve high precision radiation dose delivery. However, IMRT requires a particular attention at the target delineation step to avoid inadequate dosage to TVs/OARs. In this context, the biological information provided by PET might advantageously complete CT-Scan to refine the target delineation in HNSCC and lung cancer. Integrating PET into the treatment planning however requires the use and validation of accurate and reproducible segmentation methods, which adequately integrate the PET image properties such as the blur effect and the high level of noise. In this context, we developed specific tools, i.e. edge-preserving filters for denoising and deconvolution algorithms for deblurring that allowed the detection of gradient intensity peaks. Our gradient-based method has been validated on phantom and patient materials, and proved to be more accurate than threshold-based approaches. With this tool in hand, we demonstrated that the use of FDG-PET resulted in smaller TVs than the CT-based TVs, on both pre- and per-treatment images, and significantly improved the dose distributions to the TVs/OARs. This opens avenues for dose escalation strategies that might potentially improve the tumor local control.     

Apport de l’imagerie de spectroscopie de résonance magnétique du proton et des autres imageries métaboliques à la définition des volumes cibles de radiothérapie des tumeurs gliales de l’adulte et de l’enfant

Radiation therapy improves survival in high-grade gliomas but most patients relapse and usually within radiation fields. This may be due to uncertainties in target delineation and difficulties in identifying radioresistant regions for dose escalation. The use of T1 and T2-weighted magnetic resonance imaging (MRI) coregistration on the planning CT improves the target volume definition but magnetic resonance spectroscopic imaging (MRSI) and other types of metabolic and functional imaging (perfusion MRI, diffusion-weighted MRI, positron emission tomography (PET) imaging) may give useful additional information for target delineation. This article focuses on the potential of each imaging modality: assessment of response to treatment, detection of abnormalities not seen on MRI, predictive value for the site of local relapse. The incorporation of such techniques may improve target volume definition.     

Current status of PET/CT for tumour volume definition in radiotherapy treatment planning for non-small cell lung cancer (NSCLC)

Target volume delineation of lung cancer is well known to be prone to large inter-observer variability. The advent of PET/CT devices, with co-registered functional and anatomical data, has opened new exciting possibilities for target volume definition in radiation oncology. PET/CT imaging is rapidly being embraced by the radiation oncology community as a tool to improve the accuracy of target volume delineation for treatment optimization in NSCLC. Several studies have dealt with the feasibility of incorporating FDG-PET information into contour delineation with the aim to improve overall accuracy and to reduce inter-observer variation. A significant impact of PET-derived contours on treatment planning has been shown in 30-60% of the plans with respect to the CT-only target volume. The most prominent changes in the gross tumour volume (GTV) have been reported in cases with atelectasis and following the incorporation of PET-positive nodes in otherwise CT-insignificant nodal areas. Although inter-observer variability is still present following target volume delineation with PET/CT, it is greatly reduced compared to conventional CT-only contouring. PET/CT may also provide improved therapeutic ratio compared to conventional CT planning. Increased target coverage and often reduced target volumes may potentially result in PET/CT-based planning to yield better tumour control probability through dose escalation, while still complying with dose/volume constrains for normal tissues. Despite these exciting results, more clinical studies need to be performed to better define the role of combined PET/CT in treatment planning for NSCLC.     

Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality

PURPOSE: The goals of this study were to survey and summarize the advances in imaging that have potential applications in radiation oncology, and to explore the concept of integrating physical and biological conformality in multidimensional conformal radiotherapy (MD-CRT). METHODS AND MATERIALS: The advances in three-dimensional conformal radiotherapy (3D-CRT) have greatly improved the physical conformality of treatment planning and delivery. The development of intensity-modulated radiotherapy (IMRT) has provided the "dose painting" or "dose sculpting" ability to further customize the delivered dose distribution. The improved capabilities of nuclear magnetic resonance imaging and spectroscopy, and of positron emission tomography, are beginning to provide physiological and functional information about the tumor and its surroundings. In addition, molecular imaging promises to reveal tumor biology at the genotype and phenotype level. These developments converge to provide significant opportunities for enhancing the success of radiotherapy. RESULTS: The ability of IMRT to deliver nonuniform dose patterns by design brings to fore the question of how to "dose paint" and "dose sculpt", leading to the suggestion that "biological" images may be of assistance. In contrast to the conventional radiological images that primarily provide anatomical information, biological images reveal metabolic, functional, physiological, genotypic, and phenotypic data. Important for radiotherapy, the new and noninvasive imaging methods may yield three-dimensional radiobiological information. Studies are urgently needed to identify genotypes and phenotypes that affect radiosensitivity, and to devise methods to image them noninvasively. Incremental to the concept of gross, clinical, and planning target volumes (GTV, CTV, and PTV), we propose the concept of "biological target volume" (BTV) and hypothesize that BTV can be derived from biological images and that their use may incrementally improve target delineation and dose delivery. We emphasize, however, that much basic research and clinical studies are needed before this potential can be realized. CONCLUSIONS: Whereas IMRT may have initiated the beginning of the end relative to physical conformality in radiotherapy, biological imaging may launch the beginning of a new era of biological conformality. In combination, these approaches constitute MD-CRT that may further improve the efficacy of cancer radiotherapy in the new millennium.     

Multi-modality functional image guided dose escalation in the presence of uncertainties

Background and purpose

In order to increase local tumour control by radiotherapy without increasing toxicity, it appears promising to harness functional imaging (FI) to guide dose to sub-volumes of the target with a high tumour load and perhaps de-escalate dose to low risk volumes, in order to maximise the efficiency of the deposited radiation dose.

Methods and materials

A number of problems have to be solved to make focal dose escalation (FDE) efficient and safe: (1) how to combine ambiguous information from multiple imaging modalities; (2) how to take into account uncertainties of FI based tissue classification; (3) how to account for geometric uncertainties in treatment delivery; (4) how to add complementary FI modalities to an existing scheme. A generic optimisation concept addresses these points and is explicitly designed for clinical efficacy and for lowering the implementation threshold to FI-guided FDE. It combines classic tumour control probability modelling with a multi-variate logistic regression model of FI accuracy and an uncomplicated robust optimisation method.

Results

Its key elements are (1) that dose is deposited optimally when it achieves equivalent expected effect everywhere in the target volume and (2) that one needs to cap the certainty about the absence of tumour anywhere in the target region. For illustration, an example of a PET/MR-guided FDE in prostate cancer is given.

Conclusions

FDE can be safeguarded against FI uncertainties, at the price of a limit on the sensible dose escalation.     

Broadening the scope of image-guided radiotherapy (IGRT)

The recent wave of enthusiasm for image guidance in radiation therapy is largely due to the advent of on-line imaging devices. The current narrow definition of image-guided radiotherapy (IGRT), in fact, essentially connotes the use of near real-time imaging during treatment delivery to reduce uncertainties in target position and should therefore be termed IGRT-D. However, a broader (and more appropriate) context of image-guidance should include: (1) detection and diagnosis, (2) delineation of target and organs at risk, (3) determining biological attributes, (4) dose distribution design, (5) dose delivery assurance and (6) deciphering treatment response through imaging i.e. the 6 D's of IGRT. Strategies to advance these areas will be discussed.     

Magnetic resonance spectroscopy imaging (MRSI) and brain functional magnetic resonance imaging (fMRI) for radiotherapy treatment planning of glioma

Conventional radiotherapy of glioma is ineffective due to uncertainties in target delineation, inadequate radiation dose, and difficulties in identifying radio-resistant high-grade tumor for dose escalation. Magnetic resonance spectroscopy imaging (MRSI) and functional magnetic resonance imaging (fMRI) provide information on altered metabolic activity of tumor cells and functionally critical brain tissues, which are not available from anatomical imaging. In this paper, we review the pathological and physiological information that might be derived from MRSI and fMRI to better delineate the treatment volume and critical organs for glioma radiotherapy. Technical difficulties for incorporating MRSI and fMRI into radiotherapy treatment planning process are discussed and potential solutions are presented. A fusion protocol is used to illustrate the feasibility of registering MRSI and fMRI with simulation CT for one glioma case. An IMRT (intensity-modulated radiotherapy) dose painting plan for this case is also presented using the fused MRSI and fMRI to delineate the clinical target volumes and Broca's area.