Unterrainer et al. Radiation Oncology(2020) IEWOpen AccessRecent advances of PET imaging in clinicalradiation oncologyM. Unterrainer1,2,3*, C. Eze4, H. Ilhan1, S. Marschner4, O. Roengvoraphoj4, N. S. Schmidt-Hegemann4, F. Walter4,W. G. Kunz2, P. Munck af Rosenschöld5, R. Jeraj6, N. L. Albert1,3, A. L. Grosu7,8, M. Niyazi3,4, P. Bartenstein1,3 andC. Belka3,4AbstractRadiotherapy and radiation oncology play a key role in the clinical management of patients suffering fromoncological diseases. In clinical routine, anatomic imaging such as contrast-enhanced CT and MRI are widelyavailable and are usually used to improve the target volume delineation for subsequent radiotherapy. Moreover,these modalities are also used for treatment monitoring after radiotherapy. However, some diagnostic questionscannot be sufficiently addressed by the mere use standard morphological imaging. Therefore, positron emissiontomography (PET) imaging gains increasing clinical significance in the management of oncological patientsundergoing radiotherapy, as PET allows the visualization and quantification of tumoral features on a molecular levelbeyond the mere morphological extent shown by conventional imaging, such as tumor metabolism or receptorexpression. The tumor metabolism or receptor expression information derived from PET can be used as tool forvisualization of tumor extent, for assessing response during and after therapy, for prediction of patterns of failureand for definition of the volume in need of dose-escalation. This review focuses on recent and current advances ofPET imaging within the field of clinical radiotherapy / radiation oncology in several oncological entities (neurooncology, head & neck cancer, lung cancer, gastrointestinal tumors and prostate cancer) with particular emphasison radiotherapy planning, response assessment after radiotherapy and prognostication.Keywords: PET, Radiation oncology, Neuro-oncology, Head & neck cancer, Lung cancer, Prostate cancer, GImalignanciesIntroductionRadiotherapy plays a key role in the clinical managementof patients suffering from oncological diseases, as approximately half of cancer patients directly benefit fromindividual radiotherapy during their disease course. Inthis disease course, radiotherapy can be applied as soletreatment or as a comprehensive treatment in combination with systemic treatments such as chemotherapy or* Correspondence: [email protected] of Nuclear Medicine, University Hospital, LMU Munich,Marchioninistr. 15, 81377 Munich, Germany2Department of Radiology, University Hospital, LMU Munich, Marchioninistr.15, 81377 Munich, GermanyFull list of author information is available at the end of the articlelocal treatments such as surgery . This high clinicalsignificance for the treatment of oncological diseases isreached and maintained by the fast technologicalinnovation and improvements that were introduced andsubsequently established in clinical routine over the lastdecades , e.g. intensity-modulated radiation therapy(IMRT) has evolved as a widely used clinical treatmentmodality in many countries .Anatomic imaging such as contrast-enhanced CT andMRI are widely available and are usually used to delineate the target volume for the subsequent radiotherapy.However, in the clinical routine in radiation oncology,diagnostic issues arise that cannot be sufficiently addressed by standard morphologic imaging. In particular, The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver ) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.
Unterrainer et al. Radiation Oncology(2020) 15:88the delineation of viable tumor tissue can be challenging,especially in patients with local pretreatment such assurgery. Moreover, treatment response assessment withconventional morphological imaging is partly unable tocorrectly differentiate early relapse from radiation induced changes or inflammation, e.g. in neuro-oncology. Therefore, positron emission tomography (PET) imaging gains increasing clinical significance in the apy, as PET allows the visualization and quantification of tumoral features on a molecular level beyondthe mere morphological extent on conventional imaging,such as tumor metabolism or receptor expression. 18FFDG, a glucose analogue, is the most commonly appliedligand for oncological PET imaging  due to its provenutility and its generally increasing availability. Beyondthe visualization of glucose metabolism, other tumorcharacteristics can be targeted and visualized by PET imaging. In this regard, e.g. PET with prostate-specificmembrane antigen (PSMA) ligands are of high clinicaland scientific interest for advanced imaging of patientssuffering from prostate cancer . The tumor metabolism or receptor expression information has allowed foruse as a tool for (a) visualization of tumor extent, for (b)assessing response during and (c) after therapy, for (d)prediction of patterns of failure and for (e) definition ofthe volume in need of dose-escalation. Where, (e) sometimes has been referred to as “dose-painting” , although the idea is older  and the practice ofescalation of the PET-avid volumes has been in long usefor the treatment of e.g. head neck cancer.This review describes the recent advances of PET imaging within the field of clinical radiotherapy / radiationoncology in several oncological diseases (neuro-oncology, head & neck cancer, lung cancer, gastrointestinaltumors and prostate cancer) with particular emphasis onradiotherapy planning, but also on treatment responseevaluation and prognostication. Moreover, recent advances in PET imaging itself are reviewed with specialemphasis on the potential applicability on clinical settings in radiotherapy / radiation oncology.Neuro-oncologyPET is widely applied in the field of neuro-oncology ascomplementary imaging modality in addition to MRI. Its use may be derived from the answers to severalkey questions: 1) How to optimally define the radiotherapeutic target volume or delineate the extent of disease before surgical resection, 2) is it possible to deriveprognostic value from molecular imaging, and 3) how todistinguish treatment effect from true progression.When considering the wide field of primary CNS tumors, the entity of glioma is reported on by the PET taskforce of the Response Assessment in Neuro-OncologyPage 2 of 15(RANO) working group . This task force clearly derives evidence from published studies with validatedPET findings (either by histopathology or clinical course)in the setting of diagnosis, biopsy, surgery, radiotherapyand response assessment, and shows superiority ofamino acid PET such as 18F-FET or 11C-MET PET over 18F-FDG PET [10, 12]. Specifically, 18F-FET hasbeen shown to predict prognosis [13, 14], to enable improved target delineation [15–17] to assess treatment response . Recurrence pattern analyses havesubstantiated the role of amino acid PET in identifyingaggressive parts and the potential of targeting these regions [18–21]. In a recent study, the combination of 18FFET-PET and T1w MRI was shown to carry the most information for prediction of patterns of failure followingchemo-radiation therapy of glioblastoma patients .In the US, 18F-DOPA is a widely used tracer and it wasshown to provide additional clinical information ,which could also be validated histopathologically . Avariety of data exists on other tracers as described inTable 1 . One potential target of interest for braintumor imaging is the 18 kDa translocator protein(TSPO), as known in neurodegenerative research, withremarkable overexpression in glioblastoma patients,whereas further studies have to further elucidate thecontribution of neuro-inflammatory component withinthe signal obtained in TSPO PET [29–31]. In this regard,the potential influence of this new modality on radiotherapy approaches has to be validated. In sum, especially amino acid tracers are applied for radiotherapyplanning in clinical routine of glioma patients [9, 15, 20],but also for the differentiation of viable tumor and recurrent / progressive disease after initial radiotherapy [4,32, 33], as recently emphasized by the PET RANO group.In analogy to primary brain tumors, brain metastasescan also be visualized by PET . Although its valuefor imaging prior to radiotherapy remains unclear, PETimaging, especially with radiolabeled amino acids, hasevolved as complementary imaging tool for the differentiation of true progression from pseudoprogression, e.g.after radiotherapy [16, 35–37], see Fig. 1. Therefore, theuse of PET in brain metastases was also recently recommended by the PET RANO group .Compared to glioma and brain metastases, meningioma as extraaxial tumor is even more common. BeyondMRI, PET ligands targeting the somatostatin receptor(SSR) such as 68Ga-DOTATOC and 68Ga-DOTATATEare used in clinical routine [38, 39] and have been established for surgical guidance  or target volume definition [41, 42] due to the high expression of SSR inmeningioma tissue. Specifically, this imaging modality isof help in meningiomas at the skull base, where extraforaminal extension or osseous infiltration may be expected
Unterrainer et al. Radiation Oncology(2020) 15:88Page 3 of 15Table 1 Different tumors and tracers in neuro-oncology for different indications: target delineation (TD), prognostication (P),distinguishing between progressive disease and pseudoprogression (TR)Tumor entityTracersIndication CommentGlioma18TD/P/TRValuable as longer halftime compared to 11C-MET, high diagnostic accuracy with histopathologicalvalidation; ongoing trials to confirm clinical benefit, e. g. GLIAA 18TD/P/TRStudies on prognostic relevance and histopathological validation available, e.g. [24, 26], mainly used in theUS11TD/PStudies on prognostic relevance and histopathological validation available. Aiding in target delineation.TSPOligandsNoneInvestigational, no histopathological validation studies (ongoing)68GaDOTATOCTDAiding in target delineation or surgical approach, especially when located at the skull base68GaDOTATATETDSUV cutoff histologically validated, no relevant data available on responseBrainmetastasis18TRDifferentiation pseudoprogression/radiation necrosis vs. tumor recurrenceCNSlymphoma18NoneTumor metabolism, response assessment F-FETF-DOPAC-METMeningiomaF-FETF-FDG or in case of suspected residual or recurrent tissueafter initial therapy . Some other reports on aminoacid PET are available as well, however, in the light ofSSR-ligands, these tracers are not widely used in clinicalroutine for meningioma imaging . Beyond in CNSlymphoma , 18F-FDG PET is not recommended bythe PET RANO group for most primary brain tumors[10, 34, 46], mainly due to high background activity ofthe normal brain.Head and neck cancerHead and neck cancers (HNC) consist of a wide range oftumor entities such as squamous cell cancer, salivary tumors or nasopharyngeal carcinomas. Diagnosis andtreatment of the group of HNC is a complex and multidisciplinary approach. PET/CT provides insights intotumor biology and tissue metabolism and has an unprecedented accuracy in unmasking nodal metastases ortumor extensions. At the current state, most of the available data for PET imaging in HNC is validated for headand neck squamous cell cancer. PET/CT facilitates contouring for (chemo-) radiotherapy (CRT) and it significantly influences dose painting in radiation planning. Inabout 25% of patients with disease of unknown primary,location is revealed by 18F-FDG-PET/CT [47–52].Since HNC represents a very heterogeneous disease,there is great interest in finding prognostic markers forrisk stratification. For primary staging, the use of PET/CT leads to a change of about 10% in every TNM category and similarly, a major change in treatment strategyin about 10% of patients . This is crucial, knowingthat survival decreases by 40–50% in patients withFig. 1 A 54 years-old female patient with extensive edema on T2 MRI (a) and new contrast enhancing lesions at the temporal and occipital lobe(b) after undergoing stereotactic radiosurgery for brain metastases from malignant melanoma at both sites. MRI findings were suggestive fortumor recurrence, whereas only a faint uptake on 18F-FET PET (c) and fused PET/MRI (d) was seen in both lesions, a finding typical for radiationnecrosis. Radiation necrosis was subsequently confirmed by histopathology
Unterrainer et al. Radiation Oncology(2020) 15:88positive lymph nodes [48, 49]. Moreover, first data suggests that the use of PET/CT for radiation planningcould significantly improve the local tumor control, regional control and even survival . The maximal standardized value (SUVmax) of the primary tumor and totallesion glycolysis (TLG) of the largest node on 18F-FDGPET are PET derived parameters that can be used aspredictors of therapeutic failure and vice versa