CT in radiation oncology

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PET/CT in radiation oncology Rosa Fonti a, Manuel Conson b, Silvana Del Vecchio b,∗ a b

Institute of Biostructures and Bioimages, National Research Council, Naples, Italy Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Naples, Italy

a r t i c l e

i n f o

Article history: Received 10 May 2019 Accepted 15 July 2019 Available online xxx Keywords: PET/CT Radiotherapy planning Dose painting Adaptive radiotherapy

a b s t r a c t 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 18 F-fluorodeoxyglucose (18 F-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 18 F-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. © 2019 Elsevier Inc. All rights reserved.

Introduction By combining functional and anatomic information, positron emission tomography/computed tomography (PET/CT) provides an advantage over anatomic imaging alone in the initial staging and response assessment in cancer patients. Indeed, the widespread use of 18 F-fluorodeoxyglucose (18 F-FDG) PET/CT in oncological clinical practice has led to substantial changes in the management of many tumors as a consequence of upstaging or downstaging the extent of disease of individual patients and the recognition of responding and nonresponding tumors treated with conventional chemotherapy regimens [1-4]. Furthermore, in some instances, tar-

Abbreviations: CT, computed tomography; 64 Cu-ATSM, 64 Cu-diacetil-bis 11 11 18 18 (N4-methylthiosemicarbazone); C-MET, C-methionine; F-EF5, F-218 18 nitroimidazolpentafluoropropyl-acetamide; F-FAZA, F-fluoroazatiomycin arabinoside; 18 F-FDG, 18 F-fluorodeoxyglucose; 18 F-FDOPA, 18 F-fluorodihydroxy phenylalanine; 18 F-FET, 18 F-fluoroethyltyrosine; 18 F-FETNIM, 18 F-fluoroerythro nitroimidazole; 18 F-FLT, 18 F-fluorothymidine; 18 F-FMISO, 18 F-fluoromisonidazole; 18 F-HX4, 18 F-flortanidazole; GTV, gross tumor volume; MRI, magnetic resonance imaging; PET/CT, positron emission tomography/computed tomography; PSMA, prostate-specific membrane antigen; SUV, standardized uptake value; SUVmax , maximal standardized uptake value. ∗ Corresponding author. Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Edificio 10, Via S. Pansini, 5, Naples 80131, Italy. E-mail address: [email protected] (S. Del Vecchio). https://doi.org/10.1053/j.seminoncol.2019.07.001 0093-7754/© 2019 Elsevier Inc. All rights reserved.

geted cancer therapies have found PET/CT to be an invaluable tool for the early detection and monitoring of tumor response since the effective inhibition of the target in tumor lesions is not always associated with morpho-volumetric changes [5,6]. An additional field in which PET/CT can be helpful is radiotherapy planning and image-guided radiation delivery. Radiotherapy planning is a multistep process requiring the expertise of a multidisciplinary team that evaluates whether a malignant tumor with a given stage needs to be irradiated. Following this collegial decision, radiation oncologists establish a treatment plan including dose prescription, dose distribution, and several technical parameters for effective radiation delivery. In this process, the precise and accurate definition of target volumes is the most important step that affects all the subsequent steps and treatment outcome [7,8]. To be cured by radiation therapy, a tumor must be entirely contained within a volume of tissue receiving a predefined radiation dose. CT and/or magnetic resonance imaging (MRI) are the standard imaging modalities for anatomic delineation of target volumes. In order to maximize radiation dose to tumor tissue and minimize irradiation of normal tissues, the selected imaging modality for target volume definition should have high sensitivity to detect all involved tissues in a tumor region, and high specificity, to spare surrounding normal tissues. An additional requirement of the imaging modality for accurate target delineation is a high spatial resolution. CT, due to its

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high spatial resolution, offers detailed images of internal anatomy in 3 dimensions and allows target outlining based on density variations between neoplastic and normal tissues [9,10]. MRI provides an improved soft-tissue visualization and is preferred to CT in specific anatomic districts thus complementing CT in radiotherapy planning [9,10]. Despite the high spatial resolution of these imaging modalities, delineation of target volume remains a difficult task and a major source of inaccuracy in radiotherapy. Tumor and normal tissues may have similar density and magnetic properties thus preventing the accurate identification of tumor boundaries. Furthermore, anatomic imaging does not provide information on biological characteristics of tumors such as metabolism, hypoxia, and proliferation that may be associated with radioresistance. Integrating PET/CT findings into radiotherapy treatment planning may improve target volume definition and tumor characterization for optimal dose distribution. PET/CT can be used in radiotherapy planning, with different purposes having an increasing level of complexity and requiring specific protocols for data acquisition and transfer. The present review will focus on basic principles of PET-based target volume selection and definition using 18 F-FDG. The reported high sensitivity and specificity of 18 F-FDG PET/CT in the identification of tumor sites supported its use in radiotherapy planning with the goal of avoiding geographical misses and unnecessary irradiation of normal tissues. Furthermore, a brief overview of tracers whose uptake is associated with radioresistance will be provided to explain the development and basic principles of PET-based dose painting and adaptive radiotherapy. Finally, the use of different PET tracers for guiding radiotherapy in specific anatomic districts will be evaluated. PET-based target volume selection and definition 18 F-FDG PET/CT may be used to identify gross tumor volume (GTV) by outlining primary tumor and involved regional lymph nodes based on their increased 18 F-FDG uptake [11-13]. These volumes are then transposed on CT images that are simultaneously coregistered or acquired separately allowing the visualization of anatomic boundaries of PET-positive regions. PET-derived target volumes of primary tumors are usually reduced as compared to volumes delineated on CT alone [11]. However, the ability of PET/CT to recognize CT-undetected lymph nodes that are involved by the disease would increase PET-based volumes. Conversely, PET exclusion of tumor involvement in CT-enlarged lymph nodes would decrease PET-derived target volumes. As for anatomic imaging, the delineation method is a critical issue since any error would imply suboptimal treatment of the disease or an increased toxicity for normal tissues. In this process, a major limitation of PET imaging is its spatial resolution of about 5–7 mm that may lead to partial volume effects [14]. Due to these effects, activity in tumor lesions smaller than the resolution limit of PET will be underestimated whereas lesion size will appear larger. Despite these limitations, several delineation methods have been proposed [15,16] although standardization has not yet been achieved and more validation studies are needed. The process that recognizes and delineates an object in an image is termed segmentation. A frequently used automatic segmentation method is based on the selection of a fixed threshold [15,16]. Target and nontarget regions are identified as having a tracer uptake higher or lower than the threshold value, respectively. The threshold can be an absolute standardized uptake value (SUV) that differentiates malignant and normal tissues or can be expressed as a percentage of maximal SUV (SUVmax ) inside the tumor. In many clinical studies with 18 F-FDG, a SUV of 2.5 was set as a predefined threshold based on the assumption that background activity is around that value [17]. The most common threshold chosen for 18 F-FDG in

the clinical setting is 40%–43% of SUVmax in the target region [16]. However, an adaptation of this threshold with further information or user guidance is often needed to obtain the correct boundaries of an object especially for small lesions. Additional segmentation methods include stochastic methods that evaluate statistical differences between uptake regions and surrounding tissues, regionbased segmentation methods that exploit the homogeneity of the image to determine object boundaries and gradient-based methods that identify edges of an image as regions with a sharp change in intensity values [15,18]. No general consensus exists for the use of any of the proposed segmentation methods and the optimal delineation of tumor boundaries on PET images remains a challenging task. Despite these difficulties, previous studies have shown that integration of 18 F-FDG PET/CT in radiotherapy planning results in a better delineation of GTVs and in a reduced intra- and interobserver variability as compared to CT imaging [12]. Furthermore, in patients with different types of cancer, the selective irradiation of 18 F-FDG-positive lymph nodes was associated with a very low rate of nodal recurrences [19,20]. When PET/CT is performed for staging or response assessment purposes, the CT component of the scan can be acquired at low dose or as a high-quality diagnostic CT. A low-dose CT scan is not suitable for treatment planning. Therefore, when required for target volume definition, it is imperative that the PET/CT scan be performed with a high-quality diagnostic CT [17]. There are several options for implementing PET/CT in the planning process [21]. For instance, a low-dose whole body PET/CT can be performed for staging purposes followed by a high-quality diagnostic PET/CT over the target anatomic district for planning. When PET/CT is performed for radiotherapy planning, a number of technical aspects should be taken into account to ensure a high accuracy and reproducibility of delineated targets [22]. Patient position and immobilization devices should be the same used for radiation treatment. A flat table top, with positional aids and laser lights currently used to replicate patient position during treatment. Site-specific protocols for image acquisition should define additional requirements for a given anatomic district. For instance in head and neck cancers, the presence of many organs at risk, the physiological 18 F-FDG uptake in lymphoid tissue and the high doses frequently delivered should be taken into account for an accurate immobilization of the patient with neck support and thermoplastic mask [23]. For tumors of the thoracic district such as lung and breast cancer, target motion and artifacts due to respiration should be carefully considered [24]. Respiratory motion can cause a spatial mismatch between CT and PET images, because CT is acquired in a distinct phase of respiratory cycle whereas acquisition of PET images occurs during many respiratory cycles. Breathing artifacts can be reduced by inviting the patient to breathe shallowly during CT and PET acquisition and this approach can be used for a radiotherapy planning that does not require the exact direction and tracking of tumor motion [21]. Breathhold techniques can reduce misalignment artifacts but are not well tolerated by patients and more importantly they can be used for radiotherapy planning only when radiation dose can be delivered during the same breathing condition using a gated device [7]. A better approach is to perform a respiratory-gated PET/CT, termed 4D PET/CT, in which data are acquired into different phases in synchrony with the breathing cycle [23,24]. Respiratory motion can be monitored using different systems including a pressure sensor elastic belt placed around the abdomen, a spirometer measuring respiratory flow of air, a thermoprobe measuring the temperature of respired air, and an optical system tracking the motion of thoracic markers [25]. CT and PET images acquired in the same respiratory phase can be matched so as to avoid artifacts in attenuation correction and mislocalization of the lesion. The main advantage

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Table 1 Selected radiopharmaceuticals for radiation oncology Tracer

Biological process

Tumor type

Radiotherapy applications

References

18

F-Fluorodeoxyglucose (18 F-FDG)

Glucose metabolism, viable tumor

F-Misonidazole (18 F-MISO)

Hypoxia

Hypoxia

Lung, HN cancer

Hypoxia

Lung, HN cancer

Proliferation

Lung, HN cancer, gliomas

Amino acid metabolism Amino acid metabolism

Primary and recurrent gliomas Gliomas

GTV delineation Dose painting and adaptive radiotherapy Hypoxic subvolume delineation, dose painting and planning adaptive radiotherapy Hypoxic sub-volume delineation and spatio-temporal variations Hypoxic sub-volume delineation and spatio-temporal variations Serial proliferative tumor volume delineation before and during radiotherapy GTV delineation

[11,12,13,66]

18

All tumor types Lung, HN cancer, lymphoma Lung, HN cancer

GTV delineation and dose painting

[75-77]

Amino acid metabolism

Gliomas, paragangliomas

[80,81]

Lipid metabolism Enzymatic release of glutamate

Prostate Prostate

GTV delineation and planning dose painting GTV delineation and dose painting GTV delineation and planning dose painting

18

F-Fluoroazatiomycin arabinoside (18 F-FAZA) 18 F-Flortanidazole (18 F-HX4) 18 F-Fluorothymidine (18 F-FLT) 11

C-Methionine (11 C-MET) 18 F-Fluoroethylthyrosine (18 F-FET) 18 F-Fluorodihydroxyphenylalanine (18 F-FDOPA) 18 F-Choline 68 Ga-Prostate-specific-membrane antigen (68 Ga-PSMA)

[44-46]

[34,35,62] [36,63] [39,40,47,48]

[72-74]

[85,86] [91,93-95]

HN, head and neck; GTV, gross tumor volume.

of this technique is to provide information about the extent and trajectory of tumor motion for a more precise dose delivery. In some institutions, planning CT is acquired separately from PET/CT and in this case functional images need to be registered with planning CT images. Two methods of image registration are commonly used, namely rigid and deformable registration [23]. Rigid registration algorithms rotate and translate the CT from PET/CT and planning CT to optimize their alignment. The resulting spatial transformation is then superimposed to the corresponding PET image. Differences in patient position may be compensated using deformable registration algorithms that using morphologic changes allow the optimal alignment of 2 CT images. PET tracers and radioresistance Beyond its ability to identify tumor sites with high sensitivity and specificity, 18 F-FDG uptake often correlates with tumor grade, stage, cell proliferation, response to therapy, and prognosis [26]. By analyzing the location of recurrences after radiotherapy alone or in combination with chemotherapy, previous studies reported that areas of high 18 F-FDG uptake in pretreatment scans were preferential sites of tumor relapse in patients with different types of tumors including non-small cell lung cancer [27,28] and head and neck cancer [29]. These observations provided the rationale to use 18 F-FDG to identify regions inside the tumor most likely to be radioresistant that may need higher doses for a durable local tumor control. In addition to 18 F-FDG, other PET tracers have been evaluated to identify regions inside the tumor most likely to be radioresistant and as a guide for nonhomogeneous dose distribution within defined target volumes (Table 1). Tumor hypoxia is known to be an important factor conferring resistance to radiotherapy and correlating with treatment failure [30,31]. In fact, the low oxygen tension in hypoxic cells protects them from the effects of ionizing radiation allowing at the same time clonogenic survival leading to subsequent tumor regrowth and metastatic spread [32]. Substantial hypoxic areas can be present in many tumors especially in head and neck and lung tumors [30,31]. Hypoxia PET tracers provide a 3-dimensional distribution of hypoxic areas in a noninvasive manner. 18 F-fluoromisonidazole (18 F-FMISO) was the first and is the most extensively studied PET tracer for imaging hypoxia [33]. Under hypoxic conditions, this nitroimidazole derivative is reduced

by intracellular nitroreductase to oxygen radicals that bind to cellular macromolecules and therefore remain trapped in hypoxic tumor cells [33]. However due to the high lipophilicity of 18 FFMISO and its consequent slow plasma clearance, imaging should be performed 2–4 hours after tracer administration so as to obtain a quite low tumor-to-background ratio [30,33]. Therefore, secondgeneration nitroimidazole derivatives were developed such as 18 F-fluoroazatiomycin arabinoside (18 F-FAZA) that is more hydrophilic than 18 F-FMISO thus reaching higher tumor-tobackground ratio and having better specific activity, specificity, and also more chemical stability upon injection [34,35]. Other fluorinated nitroimidazole derivatives have also been tested including 18 F-fluoroerythronitroimidazole (18 F-FETNIM) and 18 Fflortanidazole (18 F-HX4) which due to their lower lipophilicity have been able to achieve, similarly to 18 F-FAZA, a higher tumor-tobackground ratio than 18 F-FMISO in head and neck, esophageal and lung cancer [36,37]. Finally, 18 F-2-nitroimidazolpentafluoropropylacetamide (18 F-EF5) was found to be predictive of local recurrence in lung tumors treated with highly conformal radiotherapy [38]. A different type of PET hypoxia tracer that can be labeled with various copper isotopes is 60,61,62,64 Cu-diacetil-bis(N4methylthiosemicarbazone) (60,61,62,64 Cu-ATSM). The mechanism of uptake of this tracer is not yet completely understood, it is believed that under hypoxic conditions bioreductive enzymes reduce Cu (II) to Cu (I) which dissociates from ATSM remaining trapped by intracellular proteins within the hypoxic cell [32]. In addition to altered glucose metabolism and hypoxia, increased cellular proliferation is another fundamental characteristic of tumors. In radiotherapy planning, identification of the tumor growth fractions can be useful as a potential guide for modulation of radiation dose delivery during the course of radiotherapy [39,40]. Surviving tumor cells, in fact are triggered to repopulate more effectively during the intervals between treatments leading to potential treatment failure [32]. The PET tracer 18 Ffluorothymidine (18 F-FLT) is a radiolabeled thymidine analogue that allows monitoring of thymidine kinase activity, a surrogate marker for tumor cell proliferation [41,42]. As compared to 18 FFDG, this tracer has less uptake in inflammatory tissue. This can be advantageous in highly inflammatory cancers such as head and neck carcinomas in which 18 F-FDG PET can lead to false positive results and overestimation of the GTV of the primary tumor [43].

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PET-based dose painting The integration of functional imaging in radiotherapy planning lead to the concept of dose painting that consists in delivering higher doses of radiotherapy to subregions of the planning target volume that could be responsible for local radioresistance, as defined by metabolic or functional imaging. These subregions may be identified for instance as the highly metabolically active subvolumes in the GTV delineated by 18 F-FDG PET scan [11-13] or as the hypoxic fraction within the tumor as defined by PET scan performed with hypoxia tracers [44-46] or even as highly proliferating regions detected by 18 F-FLT PET [39,40,47,48]. The rationale of this approach relies on the fact that radiation sensitivity is heterogeneous within the tumor due to the biological heterogeneity of tumor cells and this may affect local tumor response to a radiation dose that is conventionally homogeneous in the whole tumor [49]. The use of 18 F-FDG, hypoxia tracers, and 18 F-FLT may help to identify intratumoral regions containing more radioresistant cells that require a higher radiation dose to be killed. A dose escalation is possible in the functional target subvolumes using intensity-modulated radiotherapy with the aim to improve local tumor control. There are essentially 2 strategies proposed for image-guided dose escalation. Using dose painting by contours, the dose to the radioresistant regions of the tumors is increased uniformly so that all voxels of the functionally delineated volume receive the same dose while at the same time taking care to not exceed the tolerance limits of surrounding normal tissues [50,51]. This strategy can be realized by applying an additional dose to the radioresistant subvolumes thus increasing the integral tumor dose. Alternatively, a dose redistribution can allow one to prescribe an increased dose to the radioresistant regions while the mean tumor dose is maintained constant and equal to the conventional uniform dose. This means that radiosensitive regions of the tumor receive a reduced dose compared to the conventional dose. Tumor dose redistribution can be useful when integral tumor dose cannot be increased due to normal tissue constraints. Using dose painting by numbers, a specific radiation dose is prescribed to each voxel according to the value of the imaging biomarker in that voxel [50,51]. This strategy requires a prescription function that describes the mathematical relationship between the value of the imaging biomarker and the dose required to obtain a given biological effect [51]. Although several studies have shown the theoretical feasibility of this approach, most clinical studies have adopted arbitrary prescription functions such as a linear relationship between the image voxel signal and the dose [50]. Both dose painting by contours or by numbers are suitable for focal dose escalation to small radioresistant subvolumes inside the tumor that limit the risk of toxicity for normal tissues [52]. This may constitute an advantage for some anatomic districts such as head and neck that presents several normal tissue constraints and organs at risk. Despite the tremendous conceptual efforts in developing functional image-based dose painting, the clinical realization of these approaches is very demanding and clinical studies performed thus far have shown the feasibility of these methods but included only a limited number of patients (Table 2). Clinical studies with 18 F-FDG have been performed especially in patients with lung cancer [53-55] and head and neck tumors [56,57]. In lung cancer patients, 18 F-FDG-guided dose escalation resulted in higher doses to the primary lung tumor and regional lymph nodes as compared to conventional treatment plans without violating normal tissue constraints [53]. However, a higher toxicity profile was reported for patients treated with dose escalation as compared to those treated with a conventional schedule [58]. In head and neck tumors, a clinical study compared 18 F-FDG-driven dose painting by

contours to dose escalation by numbers and found that the latter resulted in less toxicity and in a clinical outcome comparable to conventional radiotherapy strategies [59]. Previous studies reported the use of hypoxia PET imaging for dose painting in patients with different malignancies including head and neck cancer and lung tumors [46,60]. In head and neck cancer patients, a planned interim analysis of a randomized phase II clinical trial reported that 18 F-FMISO-guided dose escalation in hypoxic tumors at the baseline scan improves local regional tumor control without excess toxicity [60]. In lung cancer patients, a multicenter phase II study was designed to deliver escalated doses to 18 F-MISO-positive tumors and standard doses to 18 F-MISO-negative tumors [46]. The response rate at 3 months was 50% in FMISOpositive tumors and 70/% in FMISO-negative tumors. In a subgroup of FMISO-positive patients receiving standard doses, the response rate was 50%. The authors concluded 18 F-MISO uptake is associated with a poor prognosis that cannot be reversed by escalated RT doses. In another study, FAZA-guided dose escalation to hypoxic subvolumes was planned without affecting the dose metrics of surrounding normal tissues as compared to homogeneous dose delivery [61]. However, it should be pointed out that the spatiotemporal instability of hypoxic areas during the course of therapy represents one of the main obstacles to be overcome [34-36,62,63]. Larger clinical trials are currently ongoing to establish whether dose painting and dose escalation to hypoxic regions can improve tumor control without causing important side effects, thus promoting hypoxia PET imaging in daily clinical radiotherapy guidance. PET-based adaptive radiotherapy With the progressive integration of anatomic and functional imaging in radiotherapy planning, a new concept emerged for developing more personalized radiotherapy protocols in individual patients, namely adaptive radiotherapy [64]. Anatomic variations usually occur inside the irradiated volumes in response to treatment and they can be visualized by CT or MRI. When assessed at the end of therapy, morpho-volumetric changes are used as surrogate end points of treatment efficacy. Adaptive radiotherapy consists in the adaptation of radiotherapy protocols to these anatomic variations so that the dose delivered to the target is adjusted over time depending on the tumor response [64]. In addition to anatomic variations, metabolic and functional changes are often observed early during radiotherapy. Although metabolic and functional variations in response to treatment are not included in the international criteria of tumor response except for lymphoma patients, they may be taken into account to adapt radiotherapy protocols over time [65,66] so that regions with persistent or increased 18 F-FDG uptake can receive higher doses than regions with decreased or absent tracer uptake. Similarly, dose delivered can be adjusted over time for regions with residual hypoxia as assessed by PET with dedicated tracers. Clinical trials of adaptive radiotherapy are currently limited due to the need for repeated acquisitions of imaging studies and frequent revision of the treatment plan both requiring strong technical, computational, and logistic efforts [56,57,67]. The clinical realization of functionally adaptive radiotherapy depends on the accurate delineation of radioresistant subvolumes during treatment and on the high reproducibility of the functional signal over time [68,69]. Previous studies have shown that delineation of PET-based GTVs is feasible using different tracers during treatment but increasing difficulties are encountered at later time points [70]. When using 18 F-FDG, treatment induces a progressive decrease of tracer uptake and SUVmax in the tumor whereas background uptake may be increased due to radiation-induced inflammation. Similarly, reoxygenation of tumor tissue due to radiation therapy causes a decreased uptake of hypoxia tracers and consequently a

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Table 2 Selected clinical studies performed in cancer patients using PET-based dose painting and adaptive radiotherapy Clinical study

Tracer (threshold or delineation method)

Tumor type

Number patients

Scan time

Van Elmpt et al (2012) [53]

18 F-Fluorodeoxyglucose (SUV ≥50% SUVmax )

NSCLC

20

Preirradiation

Kong F-M et al (2017) [67]

18 F-Fluorodeoxyglucose (tumor-to-aorta ratio ≥1.5)

NSCLC

42

Preirradiation and mid-treatment

Wanet M et al (2017) [54]

18 F-Fluorodeoxyglucose (gradient-based method) 18 F-Fluorodeoxyglucose (SUV ≥50% SUVpeak )

NSCLC

13

Preirradiation

NSCLC

30

Preirradiation

Moller DS et al (2017) [55]

Duprez F et al (2011) [56]

18 F-Fluorodeoxyglucose (SUV ≥50% SUVmax )

HN cancer

21

Preirradiation and after 2 weeks

Berwouts D et al (2013) [57]

18 F-Fluorodeoxyglucose (SUV ≥50% SUVmax ) 18 F-Misonidazole (combined perfusion and hypoxia parameters M ≥1)

HN cancer

10

HN cancer

25

Preirradiation and after 2 and 4 weeks Preirradiation and after 3 weeks

Vera P et al (2017) [46]

18 F-Misonidazole (SUV ≥1.4)

NSCLC

54

Preirradiation and after 5 weeks

Piroth MD et al (2012) [77]

18 F-fluoroethylthyrosine (tumor-to-brain ratio ≥1.6)

Gliomas

22

Preirradiation

Schlenter M et al (2018) [86]

18 F-Choline (tumor-to-background ratio ≥2)

Prostate

134

Preirradiation

Welz S et al (2017) [60]

Comments Randomized phase II dose-escalation trial. Acute and late toxicities are reported in ref. [58] Phase II clinical study. The 2-year rates of infield and overall local regional tumor controls were 82% and 62%, respectively One and 2-year local progression-free survival rates were 76.9% and 52.8%, respectively Randomized phase III trial. Study design and dosimetric results of the first 30 patients are reported Phase I dose-escalation trial. 18F-FDG-based target volumes significantly decreased during radiotherapy. Dose escalation to smaller target volumes at adaptation resulted in less severe toxicity Two adaptation steps using 18F-FDG PET/CT are feasible Randomized phase II trial interim analysis. Radiotherapy in nonhypoxic tumors showed better local tumor control. Dose escalation was not associated with increased toxicity Response rate at 3 months was 50% in FMISO-positive and 70/% in FMISO-negative tumors. In FMISO-positive tumors, escalated and standard doses gave the same rate of response (50%) Prospective phase II study. Median overall survival and disease-free survival were 14.8 and 7.8 months, respectively Prospective cohort study. The 5-year biochemical tumor control was 92% v 85% in patients receiving PET-based escalated dose v those treated with conventional RT

SUV, standard uptake value; HN, head and neck; NSCLC, non-small cell lung cancer.

decreased tumor-to-background ratio [36]. In both cases, simple threshold-based methods of GTV delineation may not be sufficient for accurate segmentation and, considering also the heterogeneity of response within the tumor, more robust and advanced imaging segmentation methods should be used. For instance, gradientbased methods are independent from the maximal uptake value inside the tumor and recognize boundaries of an object using the sharp change in signal intensity occurring at the edge [18]. Another important question raised by the introduction of adaptive radiotherapy is when and how often functional imaging needs to be repeated for revision of the treatment plan. In most studies using PET for adaptation, scans were repeated in the second and fourth week of treatment. One adaptation point at 2 weeks was reported in a clinical trial of dose escalation in patients with head and neck cancer [56], whereas another study in patients with the same malignancy reported 2 adaptation steps at 2 and 4 weeks [57]. Treatment adaptation reduced the target volumes at both 2 and 4 weeks. The implementation of more frequent and even daily adaptation steps is challenging since the whole process requires many complex and time-consuming procedures including image acquisition, registration and segmentation, radiotherapy planning and cumulative dose assessment [64]. The development of an image-guided radiotherapy system integrated with CT, MRI, or PET allows the automation of these procedures so that daily adaptation of target volumes and doses become possible. For instance, a radiotherapy

delivery Linac with on-board cone beam CT or in-room CT is able to perform a daily deformable delineation of target volumes and an automated daily dose evaluation. More recently, hybrid MRILinac systems can allow daily assessment of tumor geometry and the use of functional parameters derived from perfusion, diffusion, and spectroscopy imaging for dose painting and adaptation [7]. A Linac with on-board PET imaging has been recently introduced and seems promising but its clinical use has not yet been exploited [71]. Other PET tracers for image-guided radiotherapy In addition to 18 F-FDG, 18 F-FLT, and hypoxia tracers, other PET radiopharmaceuticals can trace further aspects of neoplastic diseases that can be exploited for image-guided radiotherapy of tumors in specific anatomic districts (Table 1). For instance, PET imaging with radiolabeled amino acids is based on the differential uptake of circulating amino acids between malignant and nonmalignant cells [13]. These compounds are usually labeled with 11 C such as 11 C-methionine (11 C-MET) or with 18 F resulting in unnatural amino acids such as 18F-fluoroethyltyrosine (18 F-FET) and 18 F-fluorodihydroxyphenylalanine (18 F-FDOPA) which show higher metabolic stability therefore avoiding the formation of metabolites and consequent decrease in tumor specificity [32]. In radiation treatment planning, the role of 11 C-MET PET and 18 F-FET PET has been studied especially in both high- and low-grade gliomas

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[72-77]. In brain tumors, in fact the main drawback of 18 F-FDG PET imaging is the high background due to FDG uptake by normal brain tissue [13]. On the other hand, amino acid PET imaging can integrate information obtained with standard MRI by detecting areas at higher risk of recurrence, which can benefit from a more accurate delivery of dose-escalated radiotherapy [77]. This can be of aid for such radioresistant tumors as gliomas for which routine doseescalation strategies have largely been inadequate [13]. At present, 11 C-MET is one of the best PET tracers for delineating brain tumor contours in primary and especially residual brain tumors thus complementing MRI-derived information [72]. Some studies have also evaluated stereotactic dose delivery strategy based on 11 C-MET PET in an effort to reduce treatment volume and consequent potential toxicities [74]. In addition to brain tumors, 11 C-MET PET/CT imaging has also been evaluated in radiation treatment planning of pharyngolaryngeal squamous cell carcinoma; however, high tracer uptake in normal pharyngeal mucosa and salivary glands surrounding the tumor emerged as the main drawback [78]. When the contribution of 18 F-FET PET to radiation treatment planning in high-grade glioma was evaluated, it was concluded that this tracer can significantly change the delineation of GTV and functional subvolumes during the course of treatment [79]. 18 F-FDOPA has been widely used for evaluating the dopaminergic brain system [32]. Beside physiological accumulation of tracer in the substantia nigra and striatum, it shows high uptake in primary brain tumors via the L-amino acid transporter system [32]. 18 F-FDOPA has been used for postoperative radiotherapy planning including the administration of escalated dose to 18 F-FDOPA-based volumes [80,81]. In addition to brain tumors, 18 F-FDOPA has also been used for imaging extracranial neoplastic diseases based on the expression in many tumors of neuroendocrine origin of the enzyme aromatic amino acid decarboxylase for which 18 F-FDOPA is a substrate [82]. Another metabolic pattern that can be detected in tumors by PET imaging is lipid synthesis and uptake. In fact, the accumulation of 11 C or 18 F radiolabeled choline is increased in tumors due to the increased expression and activity of choline transporters and choline kinase in neoplastic malignancies such as prostate cancer [83]. 18 F-FDG PET/CT has a low sensitivity in prostate cancer primarily due to its usually rather slow growing rate and to the proximity of the bladder and urinary tracts that generate a lot of background [84]. Therefore, 18 F-choline has become the PET tracer of choice in the management of patients with a diagnosis of prostate cancer including radiation treatment planning and PET-based dose painting [85,86], where its role has been evaluated in both the primary and recurrent settings. In the initial staging, radiolabeled choline has a limited accuracy in differentiating tumor from benign hyperplasia or chronic prostatitis and limited sensitivity in detecting small metastatic lymph nodes whose elective irradiation is quite controversial due to potential toxicity to the bladder. Despite that, especially in intermediate- and high-risk prostate cancer 18 F-choline PET/CT may detect occult nodal metastases that could be included in a conventional irradiation field or receive a boost dose delivery [87]. In prostate cancer restaging, radiolabeled choline has been shown to be effective especially when, after radical prostatectomy, tumor recurrence is suspected based on the increase of prostate specific antigen (PSA) levels [88]. In this setting, accurate estimation of disease extent is crucial for radiotherapy planning as patients with only a local recurrence can still be cured with salvage radiation therapy. In this setting, 18 F-choline PET/CT could be of help, in addition to multiparametric MRI, by detecting local recurrence within the resection bed or metastases to regional lymph nodes which can be included in the target irradiation volume with or without a dose boost to sites seen as positive on 18 F-choline PET/CT scans, allowing for more effective treatment [89,90]. A drawback in the use of radiolabeled choline for the detection of prostate tumor recurrence is

its dependence on PSA levels with lower detection rates in cases where PSA levels are below 2 ng/mL [88]. Consequently, new PET tracers have been developed for prostate cancer detection. One of the most promising seems to be the 68 Ga radiolabeled prostate-specific membrane antigen (PSMA) ligand that binds to a transmembrane glycoprotein overexpressed by prostate cancer cells [89,91]. Based on the high sensitivity of 68 Ga-PSMA PET to identify intraprostatic lesions [92], this tracer has been used to delineate GTV in radiotherapy planning of primary prostate cancer [93,94]. Planning studies also reported the potential benefit of 68 Ga-PSMA PET-based dose escalation to primary tumors [95]. A potential additional role of 68 Ga-PSMA PET is in planning salvage radiotherapy in cases of biochemical recurrence by allowing a more accurate and prompt radiotherapy guidance [89,91]. Conclusion The ability of PET/CT to visualize and characterize different biological features of tumors can be exploited to guide radiation therapy in individual patients. Several studies provided consistent evidence that integration of 18 F-FDG PET/CT in radiotherapy planning improves delineation of target volumes and reduces the uncertainties and variabilities of anatomic delineation of tumor sites. Dose painting and adaptive radiotherapy using different tracers are feasible strategies but further prospective clinical trials are needed to demonstrate their benefit in terms of local tumor control, survival, and reduced toxicity. To this end, standardization and harmonization of imaging procedures are mandatory if one has to achieve reliable comparisons of results obtained across different institutions. Finally, the development of image-guided radiotherapy systems that integrate MRI or PET are expected to overcome the technical, computational, and logistic difficulties of adaptive radiotherapy thus promoting the full integration of functional imaging in radiation therapy. Acknowledgment This work was partly supported by AIRC, Associazione Italiana per la Ricerca sul Cancro (project no. IG-17249) and by POR Campania FESR 2014–2020, SATIN grant. Declaration of Competing Interest None. References [1] El-Galaly TC, Gormsen LC, Hutchings M. PET/CT for staging; past, present, and future. Semin Nucl Med 2018;48:4–16. [2] Fletcher JW, Djulbegovic B, Soares HP, et al. Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med 2008;49:480–508. [3] Pinker K, Riedl C, Weber WA. Evaluating tumor response with FDG PET: updates on PERCIST, comparison with EORTC criteria and clues to future developments. Eur J Nucl Med Mol Imaging 2017;44:55–66. [4] Cheson BD. PET/CT in lymphoma: current overview and future directions. Semin Nucl Med 2018;48:76–81. [5] Gerwing M, Herrmann K, Helfen A, et al. The beginning of the end for conventional RECIST—novel therapies require novel imaging approaches. Nat Rev Clin Oncol 2019;16:442–58. [6] de Vries EGE, Kist de Ruijter L, Lub-de Hooge MN, et al. Integrating molecular nuclear imaging in clinical research to improve anticancer therapy. Nat Rev Clin Oncol 2019;16:241–55. [7] Beaton L, Bandula S, Gaze MN, et al. How rapid advances in imaging are defining the future of precision radiation oncology. Br J Cancer 2019;120:779–90. [8] Gregoire V, Mackie TR. State of the art on dose prescription, reporting and recording in intensity-modulated radiation therapy (ICRU report No. 83). Cancer Radiother 2011;15:555–9. [9] Evans PM. Anatomical imaging for radiotherapy. Phys Med Biol 2008;53:R151–91. [10] Zou W, Dong L, Kevin Teo BK. Current state of image guidance in radiation oncology: implications for PTV margin expansion and adaptive therapy. Semin Radiat Oncol 2018;28:238–47.

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