Pauline Trémeaux
email: tremeaux.p@chu-toulouse.fr

Sébastien Lhomme

Florence Abravanel

Stéphanie Raymond

Catherine Mengelle

Jean-Michel Mansuy

Jacques Izopet

Evaluation of the Aptima™ transcription-mediated amplification assay (Hologic®) for detecting SARS-CoV-2 in clinical specimens

Keywords: SARS-CoV-2, COVID-19, coronavirus, Hologic ® Panther System

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Background

The emergence of a new severe acute respiratory syndrome coronavirus (SARS-CoV-2) in late 2019 and its rapid spread worldwide led to over 6 million cases of coronavirus disease 2019 (COVID-19) by 1 June, 2020 [START_REF] Zhu | A Novel Coronavirus from Patients with Pneumonia in China[END_REF][START_REF]Coronavirus (COVID-19) Situation Report[END_REF]. As the rapid identification of infected individuals and their isolation is essential to prevent the spread of the disease, it became necessary to develop accurate, easy-to-use molecular diagnostic assays. Virology laboratories first developed and published in-house techniques [START_REF] Corman | Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR[END_REF][START_REF]Molecular assays to diagnose COVID-19: Summary table of available protocols[END_REF], which were soon followed by commercial assays. These must be validated on clinical specimens in addition to preliminary tests on culture lysates/supernatants or serially diluted RNA transcripts. Nasopharyngeal swabs are generally used for diagnosing viral respiratory tract infections, while deeper samples, such as tracheal aspirations or broncho-alveolar lavage fluids are used only in severe cases [START_REF] Tang | Laboratory Diagnosis of COVID-19: Current Issues and Challenges[END_REF].

Objectives

This study evaluates the performance of the automated commercial Aptima™ SARS-CoV-2 assay (Hologic® Panther™ System) on clinical samples. This test, which uses transcription-mediated amplification (TMA) to detect SARS-CoV-2, was compared to two in-house reverse transcriptasepolymerase chain reaction (RT-PCR) assays we presently use to diagnose COVID-19.

Study design

Samples

We tested 200 respiratory samples (198 nasopharyngeal swabs and 2 tracheal aspirations) from patients suspected of having COVID-19 in April and May 2020 (54.5% men; median [IQR] age: 61 [38-83] years). Half of the samples were tested with all three assays in parallel. These were the prospective samples (98 nasopharyngeal swabs + 2 tracheal aspirations). The remaining 100 nasopharyngeal swabs were selected based on the results obtained with the Panther Fusion™ module in open access (see below). They included 25 samples that were negative, 25 that were positive with a cycle threshold (Ct) value > 35, 25 that were positive with a Ct of 25-35, and 25 that were positive with a Ct < 25. These retrospective samples had been stored at -20°C for up to 43 days.

Methods

The Aptima™ SARS-CoV-2 assay was performed following the manufacturer's instructions. Virus transport medium (500 µL) was manually placed in the Panther™ tube containing 710 µL of lysis buffer.

The instrument used 360 µL of this mix for the lysis and capture of nucleic acids. The Aptima™ assay targets two virus sequences located on the ORF1ab gene. An internal control was included.

Our two in-house assays that both target virus sequences on the SARS-CoV-2 RNA-dependent RNApolymerase (RdRp) gene, use primers and probes (IP-2 and IP-4) and amplification programs from the Institut Pasteur, Paris (4). The first assay uses the MagNA Pure 96 instrument (Roche Diagnostics) to extract nucleic acids from 200 µL of virus transport medium eluted in 100 µL. RT-PCR is then performed on the Light-Cycler 480 instrument (LC480) (Roche Diagnostics) using the AccuStart™ Taq DNA polymerase (QuantaBio) and 2 µL of nucleic acids (total reaction volume: 10 µL). The second assay uses the same primers and probes on the Panther Fusion™ module (Hologic®) in open access. Samples were prepared as described above for the Aptima™ assay.

Data analysis

Because there is no reference standard method for the detection of SARS-CoV-2, we calculated the concordance between assays by using Cohen's kappa coefficient (κ), the positive percent agreement, the negative percent agreement and overall percent agreement, all with 95% confidence intervals (6, 7).

Results and discussion

Prospective study

The prospective study provided 2 positive and 98 negative samples, and there was perfect concordance between results of the Aptima™ assay and those of the Panther Fusion™ assay and very good concordance between the Aptima™ assay and the MagNA/LC480 assay. One sample was faintly positive with the MagNA/LC480 assay (virus IP-4 target, Ct = 39.97 and IP-2 -ve) and negative with the other two assays (sample A2 0141 0134, cf. Table S1 in Supplementary materials).

Retrospective study

All positive samples with Ct values < 35 (n = 50) with the Panther Fusion™ assay tested positive with the other two assays. The MagNA/LC480 assay detected only one virus target (IP-4) in 6 of these samples (initial Ct: 32-35) (cf. Table S2 in Supplementary materials).

The 25 (Ct > 35) positive samples detected by the Panther Fusion™ assay included 20 (80%) samples that were positive with The Aptima™ assay and 17 (68%) that were positive with the MagNA/LC480 assay. These latter included 13 (65%) in which only one virus target (IP-4) was detected. Five (20%) samples were negative with the Aptima™ assay and eight (32%) with the MagNA/LC480 assay, four of these were negative with both assays. These nine samples were tested again with the Panther Fusion™ assay since sample storage can result in the partial degradation of virus RNA, and thus to reduced assay sensitivity. Four were negative and five were positive or inconclusive (three with only IP-2, one with only IP-4 and one with both targets) (cf. Table S2). These discrepancies could also be due to selection bias -samples were chosen based on the Panther Fusion™ assay results.

All the Panther Fusion™ assay negative samples were also negative with the Aptima™ assay, except for one invalid sample. One sample was positive with the MagNA/LC480 assay, but displayed atypical PCR curves. A second RT-PCR on the same nucleic acid extract was negative (sample A2 0139 3655, cf. Table S2).

Concordance between assays

The invalid rate, all results included, with the Aptima™ assay was 0.5% ( Table 1).

The Aptima™ SARS-CoV-2 TMA assay was given emergency use authorization by the United States Food and Drug Administration (8) and the CE mark for in vitro diagnostic use in Europe.

We conclude that the results of the commercial Aptima™ SARS-CoV-2 TMA assay agreed very closely with those obtained with our in-house assays. It includes an internal control to detect inhibition of amplification. The Panther™ instrument also provides random access, which allows urgent samples prioritization to obtain results within 3.5 hours with the Aptima™ assay, and can deliver up to 60 results per hour. This can help laboratories provide rapid, high-throughput diagnosis during the COVID-19 pandemic crisis.

Competing interests

None declared.

Funding

  1/200). The Aptima™ and Panther Fusion™ assays gave a Cohen's coefficient κ = 0.978 [0.949-1.000], a positive percent agreement = 97.3% [95.0-99.6%], a negative percent agreement = 100% [100-100%] and an overall percent agreement = 99.0% [97.6-100%] after re-testing of discrepancies. The Aptima™ and MagNA/LC480 assays had a Cohen's coefficient κ = 0.945 [0.898-0.993], a positive percent agreement = 98.6% [96.9-100%], a negative percent agreement = 96.9% [94.5-99.3%] and an overall percent agreement = 97.5% [95.3-99.7%]. The MagNA/LC480 and Panther Fusion™ assays had a Cohen's coefficient κ = 0.956 [0.914-0.999], a positive percent agreement = 94.5% [91.4-97.7%], a negative percent agreement = 100% [100-100%] and an overall percent agreement = 98.0% [96.1-99.9%] (cf.

Table 1 .

 1 Concordance of qualitative results.

	A. Aptima™ and Panther Fusion™ assays
	Aptima™	\ Panther Fusion™ Positive Negative	Total
	Positive		72	0	72
	Negative		2	125	127
	Total		74	125	199*
	B. Aptima™ and MagNA/LC480 assays
	Aptima™	\	MagNA/LC480 Positive Negative	Total
	Positive		68	4	72
	Negative		1	126	127
	Total		69	130	199*
	C. MagNA/LC480 and Panther Fusion™ assays
	MagNA/LC480 \ Panther Fusion™ Positive Negative	Total
	Positive		69	0	69
	Negative		4	127	131
	Total		73	127	200

*One of the 200 samples was invalid with the Aptima™ assay.

Table S2 .

 S2 Retrospective study: detailed results

		Panther Fusion™		MagNA/ LC480		Aptima™
	Sample ID									Remarks
		Result	IP-2 Ct IP-4 Ct	Result	IP-2 Ct	IP-4 Ct	Result	RLU
	A2 0107	Positive	17	16.3	Positive	14.61	13.94	Positive	1 184
	A2 0119	Positive	17	16.3	Positive	16.47	15.89	Positive	1 195
	A2 0101	Positive	17.2	16.6	Positive	15.97	15.43	Positive	1 199
	A2 0112	Positive	18.9	18	Positive	18	17.44	Positive	1 205
	A2 0108	Positive	20.1	18.7	Positive	20.39	19.79	Positive	1 212
	A2 0102	Positive	20.5	20.4	Positive	18.11	17.47	Positive	1 199
	A2 0104	Positive	20.7	19.8	Positive	20.29	19.75	Positive	1 165
	A2 0115	Positive	20.9	20.1	Positive	19.65	18.98	Positive	1 213
	A2 0127	Positive	20.9	20.3	Positive	19.97	19.48	Positive	1 218
	A2 0102	Positive	21.1	20.6	Positive	19.84	19.39	Positive	1 208
	A2 0109	Positive	21.3	20.2	Positive	19.09	18.49	Positive	1 196
	A2 0121	Positive	21.5	20.6	Positive	24.36	25	Positive	1 225
	A2 0102	Positive	21.6	21.1	Positive	20.37	19.77	Positive	1 176
	A2 0112	Positive	22	21.4	Positive	17.87	17.47	Positive	1 197
	A2 0134	Positive	22.2	20.8	Positive	21.45	21.04	Positive	1 162
	A2 0119	Positive	22.3	21.4	Positive	20.66	20.26	Positive	1 203
	A2 0133	Positive	22.6	21.4	Positive	20.05	19.6	Positive	1 199
	A2 0127	Positive	22.6	21.8	Positive	23.48	22.98	Positive	1 179
	A2 0134	Positive	22.9	21.1	Positive	19.31	18.83	Positive	1 160
	A2 0117	Positive	22.9	22	Positive	22.32	21.66	Positive	1 236
	A2 0110	Positive	23.8	23.1	Positive	22.61	22.09	Positive	1 177
	A2 0101	Positive	24.1	23.2	Positive	21.92	21.46	Positive	1 206
	A2 0134	Positive	24.2	22.5	Positive	21.81	21.36	Positive	1 178
	A2 0104	Positive	24.4	23.5	Positive	21.71	21.28	Positive	1 172
	A2 0110	Positive	24.9	23.9	Positive	23.93	23.46	Positive	1 169
	A2 0117	Positive	26	25	Positive	25.99	24.51	Positive	1 229
	A2 0127	Positive	26.1	25	Positive	24.88	23.44	Positive	1 183
	A2 0121	Positive	26.2	25.5	Positive	25.03	23.48	Positive	1 227
	A2 0139	Positive	26.3	25.2	Positive	25.93	24.32	Positive	1 199
	A2 0111	Positive	29.2	28.6	Positive	30.98	28.42	Positive	1 207
	A2 1030	Positive	29.4	29	Positive	29.85	27.64	Positive	1 206
	A2 0120 01268	Positive	29.9	28.8	Positive	31.99	29.29	Positive	1 176
	A2 0114	Positive	29.9	29.2	Positive	30.6	28.46	Positive	1 195
	A2 0133	Positive	30.1	30.1	Positive	28.16	26.41	Positive	1 176
	A2 0127	Positive	30.5	30.5	Positive	30.33	28.33	Positive	1 198
	A2 0112	Positive	30.6	30.1	Positive	31.1	28.77	Positive	1 188
	A2 0112	Positive	30.6	30.7	Positive	27.37	25.62	Positive	1 178
	A2 0138	Positive	30.7	29.5	Positive	29.23	26.98	Positive	1 170
	A2 0128	Positive	31	30.1	Positive	30.96	28.57	Positive	1 189
	A2 0117	Positive	31.1	30.2	Positive	31.98	28.52	Positive	1 226
	A2 0115 01876	Positive	32.3	31.4	Positive	34.03	30.6	Positive	1 205
	A2 0111	Positive	32.7	32.4	Positive	-	34.51	Positive	1 189
	A2 0111	Positive	33	32.2	Positive	-	34.69	Positive	1 163
	A2 0127	Positive	33	32.6	Positive	31.89	36.71	Positive	1 215
	A2 0112	Positive	33.3	33.4	Positive	33.85	30.34	Positive	1 199
	A2 0113	Positive	33.4	33.2	Positive	34.83	29.86	Positive	1 203
	A2 0126	Positive	33.5	32.8	Positive	-	34.24	Positive	1 053
	A2 0130	Positive	33.8	34.6	Positive	-	34.45	Positive	1 173
	A2 0123	Positive	34.3	33	Positive	-	32.57	Positive	911
	A2 0116	Positive	34.3	33.3	Positive	-	34.38	Positive	1 155
	A2 0105	Positive	35.8	36.3	Positive	36.46	32.72	Positive	1 217
	A2 0139	Positive	36.1	36.5	Positive	-	34.97	Positive	1 168
	A2 0115	Positive	36.4	36.7	Positive	37.75	32.76	Positive	1 166
	A2 0132	Positive	36.5	36	Positive	-	35.05	Positive	1 212
	A2 0102	Positive	36.8	35.2	Negative	-	-	Negative	309	Negative when re-tested in Fusion
	A2 0134	Positive	36.8	36	Positive	-	36.95	Positive	1 132
	A2 0112	Positive	37	38.8	Negative	-	-	Positive	1 219	Positive when re-tested in Fusion (IP-2 Ct = 36.9; IP-4 Ct = 37)
	A2 0126	Positive	37.1	36.8	Positive	-	36.15	Negative	381	Negative when re-tested in Fusion
	A2 0111	Positive	37.3	36	Positive	-	36.33	Positive	998
	A2 0143	Positive	37.7	35.6	Positive	-	33.53	Positive	1 187
	A2 0123	Positive	37.8	36.9	Positive	-	35	Positive	1 232
	A2 0119	Positive	37.8	39.2	Positive	-	39.73	Positive	1 219
	A2 0127	Positive	38.3	35.6	Negative	-	-	Positive	1 141	Negative when re-tested in Fusion
										Inconclusive when re-tested in
	A2 0139	Positive	38.3	38.6	Negative	-	-	Positive	828	Fusion (IP-2 Ct = 44.9, atypical
										curve; IP-4 negative)
	A2 0107	Positive	38.7	38	Positive	-	38.16	Positive	1 172

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Supplementary materials

Ct: cycle threshold, RLU: relative light unit


Isabelle Gardin
email: isabelle.gardin@chb.unicancer.fr

Methods to delineate tumour for radiotherapy by fluorodeoxyglucose positron emission tomography Méthodes de délinéation tumorale en radiothérapie par tomographie par émission de positons au fluorodésoxyglucose

Keywords: Delineation, FDG PET, Metabolic tumour volume Résumé Délinéation, TEP FDG, Volume tumoral métabolique

Introduction

Segmentation is a process of partitioning an image into a set of volumes of interest (functional, anatomical or anatomical-pathological) or extracting one, in particular. Computed tomography (CT) is the most commonly used imaging modality to define the gross tumour volume in radiotherapy.

However, studies from the literature have shown the adding value of combining positron emission tomography (PET) imaging with ( 18 F)-fluorodeoxyglucose (FDG) with CT [START_REF] Im | Current methods to define metabolic tumor volume in positron emission tomography: which one is better?[END_REF]. FDG-PET is used to identify tumour tissues with increased glucose metabolism, considered as positive tissues, compared to surrounding healthy tissues. This volume corresponds to the metabolic tumour volume. For example, Ashamalla et al. reported that metabolic tumour volume defined using PET and CT images had better interobserver reproducibility in lung cancer than gross tumour volume delineated on CT alone [START_REF] Ashamalla | The contribution of integrated PET/CT to the evolving definition of treatment volumes in radiation treatment planning in lung cancer[END_REF]. Thus, metabolic tumour volume delineation resulted in a clinically significant change in gross tumour volume in 52% of patients.

Although many studies have shown the contribution of metabolic tumour volume measurement in predicting treatment response and tumour delineation for radiotherapy treatment planning, there is no consensus on the optimal method to delineate metabolic tumour volume in FDG-PET imaging [START_REF] Im | Current methods to define metabolic tumor volume in positron emission tomography: which one is better?[END_REF][START_REF] Zaidi | PET-guided delineation of radiation therapy treatment volumes: a survey of image segmentation techniques[END_REF]. This is due to the fact that there is a significant partial volume effect in PET imaging responsible for a blurry edge at the tumour. This is illustrated in Figure 1 representing a theoretical slice of a phantom with spheres of different volumes filled with the same concentration of FDG. The corresponding PET image shows that the two smallest spheres appear to contain a lower FDG concentration than the others (Figure 1b). In addition, on the plot of the standard uptake value profile passing through a sphere, it can be seen (see Figure 1.d) that the edge of the sphere is not clearly defined and that it is difficult to know exactly where it is located. This is characterized by an area of a few voxels of thickness for which it is not known whether they belong to the tumour or to healthy tissues. In addition, glucose metabolism in the vicinity of the tumour is highly dependent on its environment. In particular, it may be of the same order of magnitude than the lesion for some healthy tissues. In radiotherapy, it is not uncommon to have hypoxic or necrotic parts within the tumour characterized by significant variations in FDG uptake complicating the segmentation task, as shown in Figure 2. All these factors, as well as the physiological movements responsible for additional blurring in the images, make the task complex.

The different metabolic tumour volume segmentation methods proposed in the literature are presented, as well as their advantages and disadvantages. Given the difficulty of solving the problem, many delineation algorithms have been proposed in the literature [START_REF] Im | Current methods to define metabolic tumor volume in positron emission tomography: which one is better?[END_REF][START_REF] Zaidi | PET-guided delineation of radiation therapy treatment volumes: a survey of image segmentation techniques[END_REF]. They are generally classified into three main approaches:

• the contour-based approach looking for sharp variations in intensity in the image, characterizing the presence of boundaries between regions;

• the region-based approach to locate homogeneous areas in the image, showing the presence of a region;

• the classifier-based approach, corresponding to classification of voxels aiming to define for each voxel to which region it belongs.

Since glucose metabolism differs from organ to organ, metabolic tumour volume segmentation methods first define a volume of interest, also called a volume of work. Usually this volume corresponds to a cube, defined manually, encompassing the tumour. Then the segmentation method is applied in this volume. As a result, some methods are not reproducible because they are sensitive to this volume of work.

Contour-based approaches

Threshold-based methods

In thresholding methods, the volume of work is divided into two categories of voxels. Those with an standard uptake value above the threshold are attributed to the tumour, and those below are considered to belong to healthy tissues. The main advantage of these methods is their simplicity of use and their speed of execution. In addition, they immediately lead to the definition of a single closed contour.

Several methods have been proposed in the literature to define the optimal threshold value.

Fixed absolute threshold

Fixed absolute thresholds of standard uptake value have been proposed in the literature to delineate metabolic tumour volume. The commonly used value is 2.5 [START_REF] Nestle | Comparison of different methods for delineation of ( 18 F)-FDG PET-positive tissue for target volume definition in radiotherapy of patients with non-small cell lung cancer[END_REF]. This value was chosen because it would correspond to a differential diagnosis between malignant and benign pulmonary nodules [START_REF] Paulino | FDG-PET in radiotherapy treatment planning: Pandora's box?[END_REF],

but it does not find its justification in image processing and generally leads to a delineation very far from the truth [START_REF] Nestle | Comparison of different methods for delineation of ( 18 F)-FDG PET-positive tissue for target volume definition in radiotherapy of patients with non-small cell lung cancer[END_REF].

Fixed relative threshold

Fixed relative thresholds, defined as a percentage of the maximum value of standard uptake in the tumour (SUVmax), are also commonly used to delineate the metabolic tumour volume. In one of the first studies conducted on the delineation of high uptake in FDG-PET imaging, Erdi et al found, on phantom, that relative thresholds of 36 to 44% allowed the accurate measurement of the sphere volume of different sizes for different contrasts [START_REF] Erdi | Segmentation of lung lesion volume by adaptive positron emission tomography image thresholding[END_REF]. As a result, the 42% value proposed by Erdi et al.

is generally used in the literature. For the sake of simplicity, some authors have rounded it down to 40%.

Other studies have shown that the use of a fixed relative threshold of 42% is appropriate when the structure is sufficiently homogeneous (in the case of a phantom), static, large and well contrasted. On the other side, it quickly reaches its limits for heterogeneous or small lesions, of low contrast or in movement [START_REF] Nestle | Comparison of different methods for delineation of ( 18 F)-FDG PET-positive tissue for target volume definition in radiotherapy of patients with non-small cell lung cancer[END_REF][START_REF] Yaremko | Thresholding in PET images of static and moving targets[END_REF]. A value of 20% was recommended for metabolic tumour volume delineation for lung tumours in the absence of respiratory gating [START_REF] Fernando | Using FDG-PET to delineate gross tumor and internal target volumes[END_REF]. The spreading and therefore the decrease in signal intensity caused by respiratory movements does not allow the 42% value recommended for static tumour to be used. In fact, a single threshold seems impossible given a movement of different breathing amplitude between patients, also depending on the location of the lung tumour.

Adaptative threshold

Figure 3 shows an example of curves showing the optimal threshold value to be applied depending on the sphere size and the contrast between the sphere and the background of a phantom. It can be seen that this threshold depends on these two characteristics. As a result, thresholding methods more complex than a fixed relative threshold value have been proposed in the literature to adapt the threshold to be applied on a case-by-case basis according to certain characteristics of the lesion such as its volume, global or local contrast, mean standard uptake value, etc. [START_REF] Erdi | Segmentation of lung lesion volume by adaptive positron emission tomography image thresholding[END_REF][START_REF] Schaefer | Impact of consensus contours from multiple PET segmentation methods on the accuracy of functional volume delineation[END_REF][START_REF] Doyeux | Reproducibility of the adaptive thresholding calibration procedure for the delineation of ( 18 F)-FDG-PET-positive lesions[END_REF].

The principle of defining the optimal threshold to be applied, is generally divided into two distinct steps: the calibration phase of the method, then the clinical use. The calibration phase consists in defining mathematical expressions to calculate the optimal threshold from preliminary phantom studies. These expressions are then used clinically for the delineation of the lesion on patient's data.

We have also shown that the calibration phase can be performed from clinical data [START_REF] Ganem | Delineation of lung cancer with FDG PET/CT during radiation therapy[END_REF].

Initial calibration of the method, followed by regular quality control, are common approaches in radiotherapy, but are not appreciated in diagnostic imaging. This partly explains the low use of these methods. In addition, the application of a threshold may exclude cold regions within heterogeneous tumour uptake, or may inadvertently include healthy tissues with a significant glucose metabolism. As a result, more advanced algorithms have been developed.

Gradient-based methods

These methods look for sharp variations in intensity in the image, characterized by strong gradients or slopes between standard uptake values of neighbouring voxels [START_REF] Shen | PET tumor segmentation: comparison of gradient-based algorithm to constant threshold algorithm[END_REF][START_REF] Geets | A gradient-based method for segmenting FDG-PET images: methodology and validation[END_REF]. These methods have several major disadvantages. They are sensitive to PET image reconstruction parameters, noise and uptake heterogeneities. It is generally difficult to obtain closed contours. Therefore, they must be associated with extensive image processing that greatly determines the performances of the algorithm and the contour obtained.

Active contour methods

In order to overcome the difficulty of obtaining closed contours with gradient-based methods, approaches based on deformable models have been proposed in image processing [START_REF] Kass | Snakes: Active contour models[END_REF]. These methods are also called active contours or "snakes". They aim at providing closed contours from the very beginning. The basic principle is to choose an initial closed contour, using for example a thresholding method, and to deform it from its initial position to an end position. Like a snake, the contour is deformed to better fit the edges of the tumour. The deformation is controlled by a function that takes into account different image characteristics.

The main disadvantage of these methods is that they remain sensitive to their initialization. Their convergence towards the final form can be slow. Active contours have been used in many image processing applications, particularly in CT imaging, by being adaptable to complex structures such as anatomical ones through the addition of deformation constraints. They seem less adapted to PET images. However, we can quote the method proposed by Abdoli et al. [START_REF] Abdoli | Contourlet-based active contour model for PET image segmentation[END_REF].

Region-based approaches

Seeded region growing methods

The seeded region growing algorithms start from an initial voxel called seed, chosen within the region to be segmented and seek to make it growing by gradually aggregating voxels according to a criterion.

The neighbouring voxels of the seed are successively examined and if they verify the aggregation criterion then they are included in the region and become new seeds. Otherwise, they are rejected. This iterative process is repeated until there are no more voxels that meet the aggregation criterion.

The proposed algorithms differ according to the method of definition of the initial seed (number and size of the seed, manual or automatic initialization) and the aggregation criterion (directions travelled, discriminant values). The latter are often based on a local criterion based on the homogeneity of the voxel intensity. It is generally expressed as an intensity range in which the intensity of the voxel studied must lie.

As with thresholding methods, these algorithms are fast. However, they do not take into account the hypoxic and necrotic areas within the tumour. The use of these methods for the segmentation of FDG positive tissues in PET imaging has been poorly reported in the literature. However, we can quote [START_REF] Green | Semiautomatic volume of interest drawing for ( 18 F)-FDG image analysis-method and preliminary results[END_REF].

Random walk algorithms

In this method, the user or algorithm defines several seeds in each of the regions of interest (here the lesion and surrounding healthy tissues). For each of the other voxels in the volume of work, the algorithm answers the following question: what is the probability that a random walker leaving this voxel will first reach one of the seeds of each region? The walker is also constrained, making it even more difficult for him to move in a direction corresponding to a significant gap between grey levels.

Then the voxel is assigned to the most likely region [START_REF] Grady | Random walks for image segmentation[END_REF].

We have shown that this algorithm is robust to metabolic tumour volume segmentation in lesions with very heterogeneous FDG uptake [START_REF] Onoma | Segmentation of heterogeneous or small FDG PET positive tissue based on a 3D-locally adaptive random walk algorithm[END_REF].

Classifier-based approaches

Given the partial results of the previous methods, many authors have focused on approaches with a very different paradigm, based on the classification of voxels, also call pattern recognition methods.

Given the very large number of methods proposed and the complexity of the algorithms, the exhaustive list of methods and their detailed description is beyond the scope of this literature review. It is possible to refer to the following articles [START_REF] Im | Current methods to define metabolic tumor volume in positron emission tomography: which one is better?[END_REF][START_REF] Zaidi | PET-guided delineation of radiation therapy treatment volumes: a survey of image segmentation techniques[END_REF].

The segmentation methods presented above analyse the data from a strictly image point of view since the elements are contours (cf. § 2. Contour-based approaches) or regions (cf. § 3. Region-based approaches). Here, we are interested in each voxel individually and try to determine to which region it belongs. More formally, it is a problem of classifying individuals (voxels) among a set of classes (volumes of interest). Each volume of interest is defined by characteristics. The goal is then for each voxel from the volume of work to study its own characteristics and compare them with the characteristics of volumes of interest to determine to which region it most likely belongs based on its degree of similarity. At the end of this pattern recognition process, each voxel is assigned a label corresponding to its volume of interest of belonging.

The process can be separated into four complementary axes, making the originality of the method:

• the definition of characteristic parameters of the voxel. In general, we are only interested in its intensity (here standard uptake value);

• the number of volumes of interest. In general, it is assumed that there are two volumes of interest [START_REF] Aristophanous | A Gaussian mixture model for definition of lung tumor volumes in positron emission tomography[END_REF][START_REF] Dewalle-Vignion | A new method based on both fuzzy set and possibility theories for tumor volume segmentation on PET images[END_REF][START_REF] Lelandais | Dealing with uncertainty and imprecision in image segmentation using belief function theory[END_REF], but it may be useful to define others, such as a volume of interest with voxels that are difficult to classify [START_REF] Hatt | Fuzzy hidden Markov chains segmentation for volume determination and quantitation in PET[END_REF];

• the definition of the characteristic parameters of volumes of interest. In most cases, this is the mean value and variance of standard uptake values from volumes of interest;

• the construction of decision rules making it possible to define for each voxel its membership of a volume of interest according to three mechanisms: assignment, rejection and non-decision. This is the voxel labelling phase. This step is most often based on a theoretical foundation, including probability theory, fuzzy theory and belief function theory [START_REF] Aristophanous | A Gaussian mixture model for definition of lung tumor volumes in positron emission tomography[END_REF][START_REF] Dewalle-Vignion | A new method based on both fuzzy set and possibility theories for tumor volume segmentation on PET images[END_REF][START_REF] Lelandais | Dealing with uncertainty and imprecision in image segmentation using belief function theory[END_REF][START_REF] Hatt | Fuzzy hidden Markov chains segmentation for volume determination and quantitation in PET[END_REF].

The principle of the methods described above does not take into account essential information when segmenting the image. Indeed, the voxels of a volume of interest are not randomly distributed in the image. On the contrary, they are connected. Several methods can be used to take this contextual information into account [START_REF] Dewalle-Vignion | A new method based on both fuzzy set and possibility theories for tumor volume segmentation on PET images[END_REF][START_REF] Lelandais | Dealing with uncertainty and imprecision in image segmentation using belief function theory[END_REF][START_REF] Hatt | Fuzzy hidden Markov chains segmentation for volume determination and quantitation in PET[END_REF].

The advantage of these methods is that they are more robust than thresholding methods to the presence of noise and heterogeneity in the image. However, they can be slower and their diffusion in clinics remains very marginal.

Discussion and conclusion

Many methods for segmentation of FDG PET positive tissues have been proposed in the literature.

Unfortunately, there is no consensus on the most accurate and robust method.

Threshold methods are widely used because of their speed of execution, ease of use and availability on PET image processing stations and treatment planning systems. A fixed relative threshold value of 42% or 40% is often proposed. While it is interesting to use, it should be applied with great caution for small tumours, low contrasts (standard uptake value below 3), or in the presence of uptake heterogeneity within the lesion, as well as for lung locations in case of significant respiratory movement of the tumour. As a result, methods using a mathematical adjustment of the optimal threshold value have been proposed in the literature. Those based on iterative approaches to determining the optimal threshold value are preferred, as they take into account the characteristics of the patient's data. Their main disadvantage is the requirement for a calibration phase specific to each PET device and PET data reconstruction parameters.

In order to overcome these limitations, much more sophisticated methods have been proposed, mainly based on voxel classification algorithms including contextual information on the neighbourhood of voxels in the same region. Unfortunately, these methods are not widely available on PET image processing stations or on treatment planning systems.

Figure 1 .

 1 Figure 1. Tumour delineation for radiotherapy by fluorodeoxyglucose positron emission tomography. a) Schematic slice of a cylindrical phantom containing spheres of different diameters filled with the same concentration of fluorodeoxyglucose. b) Corresponding positron emission tomography image. c) Theoretical profile corresponding to the line in a). d) The same profile corresponding to the positron emission tomography image b).

Figure 2 .

 2 Figure 2. Tumour delineation for radiotherapy by fluorodeoxyglucose positron emission tomography: transverse thoracic PET/TDM slice showing a lesion with a very high heterogeneity of fluorodeoxyglucose uptake.

Figure 3 .

 3 Figure 3. Tumour delineation for radiotherapy by fluorodeoxyglucose positron emission tomography: example of optimal relative threshold values to be applied, as well as the corresponding calibration curves to optimize the delineation of different spheres of different volumes and five contrasts between the background and the spheres.

Conflict of interests

The author declares that she has no conflict of interests.


Dr Pierre Decazes
email: pierre.decazes@chb.unicancer.fr

Sébastien Thureau

Romain Modzelewski

Mathilde Damilleville-Martin

Pierre Bohn

Pierre Vera

Benefits of positron emission tomography scans for the evaluation of radiotherapy Intérêt de la tomographie par émission de positrons pour l'évaluation de la radiothérapie

Keywords: Radiotherapy, positron emission tomography, monitoring, therapeutic response Radiothérapie, tomographie par émission de positons, suivi, réponse thérapeutique

The assessment of tumour response during and after radiotherapy determines the subsequent management of patients (adaptation of treatment plan, monitoring, adjuvant treatment, rescue treatment or palliative care). In addition to its role in extension assessment and therapeutic planning, positron emission tomography combined with computed tomography provides useful functional information for the evaluation of tumour response. The objective of this article is to review published data on positron emission tomography combined with computed tomography as a tool for evaluating external radiotherapy for cancers. Data on positron emission tomography combined with computed tomography scans acquired at different times (during, after initial and after definitive [chemo-]radiotherapy, during post-treatment follow-up) in solid tumours (lung, head and neck, cervix, oesophagus, prostate and rectum) were collected and analysed. Recent recommendations of the National Comprehensive Cancer Network are also reported. Positron emission tomography combined with computed tomography with ( 18 F)-labelled fluorodeoxyglucose has a well-established role in clinical routine after chemoradiotherapy for locally advanced head and neck cancers, particularly to limit the number of neck lymph node dissection. This imaging modality also has a place for the

Résumé

L'évaluation de la réponse tumorale pendant et après la radiothérapie détermine la suite de la prise en charge des patient (adaptation du plan de traitement, surveillance, traitement adjuvant, traitement de sauvetage ou soins palliatifs). En plus de son rôle dans le bilan d'extension et le planning thérapeutique, la tomographie par émission de positrons combinée à la tomodensitométrique fournit des informations fonctionnelles utiles pour l'évaluation de la réponse tumorale. L'objectif de cette revue est de compiler et résumer des données publiées sur la tomographie par émission de positrons combinée à la tomodensitométrie en tant qu'outil d'évaluation de la radiothérapie externe des cancers.

Des données sur la tomographie par émission de positrons combinée à la tomodensitométrie acquise à différents moments (pendant, après les [chimio]radiothérapies initiale et définitive, et au cours du suivi post-traitement) dans les tumeurs solides (poumon, tête et cou, col de l'utérus, oesophage, prostate et rectum) ont été recueillies et examinées. Des recommandations récentes du National Comprehensive Cancer Network sont également rapportées. La tomographie par émission de positrons combinée à la tomodensitométre au ( 18 F)-fluorodésoxyglucose a un rôle bien établi en routine clinique après la chimioradiothérapie des cancers de la tête et du cou localement avancés, notamment pour limiter le nombre de curages ganglionnaires cervicaux. Cette modalité d'imagerie a également une place pour l'évaluation de la chimioradiothérapie initiale du cancer de l'oesophage, notamment pour détecter des métastases à distance, et pour l'évaluation post-thérapeutique des cancers du col de l'utérus. Plusieurs radiotraceurs utilisés pour la tomographie par émission de positrons combinée à la tomodensitométrie, comme ceux à la choline, sont également recommandés pour les patients atteints d'un cancer de la prostate présentant un échec biochimique. La tomographie par émission de positrons combinée à la tomodensitométrie au ( 18 F)-fluorodésoxyglucose est facultative pour de nombreuses autres indications et la détermination des avantages cliniques de l'évaluation de la réponse tumorale par cette technique d'imagerie, éventuellement en association avec l'IRM, demeure un domaine de recherche très actif.

Introduction

Radiotherapy is a major modality for the treatment of many cancers. One of the key points is the identification of the target volume(s) to be treated. Anatomical imaging, including computed tomography (CT) but also magnetic resonance imaging (MRI), has a fundamental role in locating the lesions to be treated and the organs to be preserved.

Functional positron emission tomography imaging combined with computed tomography (PET/CT), mainly with ( 18 F)-fluorodeoxyglucose ( 18 FDG), also has a well-established role before radiotherapy for initial extension assessment, particularly for lung and oesophageal cancers, and for radiotherapy planning, including non-small cell lung cancer, head and neck cancer, lymphoma and oesophageal cancer [START_REF] Thureau | Interest of FDG-PET for lung cancer radiotherapy[END_REF]. PET/CT is also interesting for assessing tumour response, as the metabolic response may be earlier than the anatomical response, with the 18 FDG uptake decreasing earlier than the tumour volume [START_REF] Young | Measurement of clinical and subclinical tumour response using ( 18 F)-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group[END_REF]. However, PET/CT performed during or after radiotherapy may also be affected by treatment-related changes, such as radiation-induced inflammation uptake, potentially compromising the analysis (3).

The tumour response evaluated during radiotherapy offers the opportunity to adapt the treatment planning to a reduced target volume, to determine sub-volumes possibly defined by biological properties (e. g. proliferation or hypoxia) and to spare more organs at risk (adaptive radiotherapy). The evaluation of the tumour response after radiotherapy also determines the subsequent steps of the patient's management (monitoring, adjuvant or salvage treatment, palliative care, etc.).

The goals of PET/CT differ according to the timing of the examination compared to the radiotherapy. These different times, illustrated in Figure 1, are:

•

PET/CT during radiotherapy (interim evaluation): the objective is to modify the radiotherapy planning according to variations in volume or tumour metabolism. The time window is rather narrow, as too early PET/CT may not detect the tumour response, while too late examination may be altered by post-therapeutic inflammation while limiting the significance of a possible change in the radiotherapy plan.

• PET/CT after initial (chemo)radiotherapy to assess response and adapt subsequent treatment with, for example, the choice of a "watch and wait" policy rather than planned surgery in case of a complete response.

• PET/CT after exclusive (chemo)radiotherapy to assess response and detect early failure, at least 3 months after radiotherapy for most cancers.

• PET/CT during follow-up to detect and/or localize a relapse.

This review, updating a previous work (4), focuses on PET/CT when it is performed during radiotherapy, at the end of preoperative radiotherapy, after radiotherapy completion and during followup. As far as possible, recent recommendations from the National Comprehensive Cancer Network (NCCN) are reported for the various indications and are summarized in Table 1. We did not cover PET/CT after initial chemotherapy without radiotherapy, brain tumours, lymphomas and metastases.

PET/CT during radiotherapy (interim evaluation)

The evaluation of tumour response during (chemo)radiotherapy may pave the way for: 1/ reduction of target volumes in the event of tumour regression, 2/ reduction of the radiotherapy dose in sensitive tumours or 3/ increase in the intensity of treatment (total dose, acceleration of radiotherapy, salvage surgery...) in resistant tumours [START_REF] Vera | FDG PET during radiochemotherapy is predictive of outcome at 1 year in non-small-cell lung cancer patients: a prospective multicentre study (RTEP2)[END_REF]. In practice, the radiotherapy planning would be adapted ("adaptive radiotherapy") to the tumour response by redefining the target volume and increasing the total dose ("boost") or dose per fraction with a maintained constant treatment time ("accelerated boost"). These adaptations are possible thanks to intensity-modulated radiotherapy, where the doses delivered are of variable intensity. With this technique, complex and deliberately heterogeneous dose distributions can be obtained that target form and biological subvolume (precisely adapt to the biologic target volume). Ideally, information on tumour response is obtained early enough so that a significant part of the radiotherapy can be modified [START_REF] Van Elmpt | Therapy response assessment in radiotherapy of lung cancer[END_REF]. We present the results obtained in lung, oesophageal and head and neck cancers.

Lung

Concomitant chemoradiotherapy remains the standard treatment for locally advanced non-operable non-small cell lung cancer, with overall survival remaining low [START_REF] Johnson | Recent clinical advances in lung cancer management[END_REF][START_REF] Aupérin | Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer[END_REF]. 18 FDG PET/CT is commonly used for initial staging.

PET/CT can be performed during radiotherapy as confirmed by the analysis of 53 18 FDG serial PET/CT performed in ten patients with non-small cell lung cancer showing the absence of significant artefacts induced by radiotherapy [START_REF] Edet-Sanson | Serial assessment of FDG-PET FDG uptake and functional volume during radiotherapy (RT) in patients with non-small cell lung cancer (NSCLC)[END_REF]. A systematic review of 21 series (627 patients) concluded that the tumour response to 18 FDG PET/CT during radiotherapy ("interim PET/CT") could be used as a predictor of local control and survival in patients with non-small cell lung cancer [START_REF] Cremonesi | Role of interim ( 18 F)-FDG-PET/CT for the early prediction of clinical outcomes of non-small cell lung cancer (NSCLC) during radiotherapy or chemoradiotherapy. A systematic review[END_REF]. A decrease in the uptake of 18 FDG in the primary tumour was associated with better local control and long-term survival. This was also demonstrated by our team, which prospectively included 52 patients in a multicentre, strictly quality-controlled study comparing 18 FDG PET/CT before and during the fifth week of radiotherapy (2Gy per fraction, 10Gy per week). The maximum SUV (SUVmax) at 5 weeks was the only predictor of death or tumour progression at 1 year (odds ratio [OR] of 1.97, 95%

confidence interval [95% CI]: 1.25-3.09, p = 0.003) in multivariate analysis. A value of SUVmax at 5.3 has a sensitivity of 70% and specificity of 92% to predict tumour progression or death at one year [START_REF] Vera | FDG PET during radiochemotherapy is predictive of outcome at 1 year in non-small-cell lung cancer patients: a prospective multicentre study (RTEP2)[END_REF]. However, the systematic review mentioned above highlighted the great heterogeneity between studies, for example with regards to patient selection criteria, treatment modalities, PET/CT acquisitions, timing and predictive parameters studied [START_REF] Cremonesi | Role of interim ( 18 F)-FDG-PET/CT for the early prediction of clinical outcomes of non-small cell lung cancer (NSCLC) during radiotherapy or chemoradiotherapy. A systematic review[END_REF].

However, adaptive radiotherapy guided by PET/CT is feasible and would allow for a significant reduction in doses to normal tissues compared to traditional planning techniques [START_REF] Kelsey | Adaptive planning using positron emission tomography for locally advanced lung cancer: A feasibility study[END_REF].

A study involving 102 patients with 30 patients who received a dose adjustment according to the mid-treatment PET showed that patients who received adaptive radiotherapy had a 5-year survival rate 19% better than standard radiotherapy [START_REF] Kong | Greater reduction in midtreatment FDG-PET volume may be associated with worse survival in non-small cell lung cancer[END_REF]. However, the interoperator reproducibility of pertherapeutic tumour segmentation may be limited, and this reproducibility may be improved by an easily applicable SUVmax-based segmentation method that can be used for replanning [START_REF] Ganem | Delineation of lung cancer with FDG PET/CT during radiation therapy[END_REF].

Other radiotracers have been studied in non-small cell lung cancer with a particular interest in tumour radiobiology. This is notably the case of 18 F-labelled misonidazole ( 18 F-miso) which is a tumour hypoxia tracer, strongly associated with in vitro radioresistance or 18 F-fluorothymidine ( 18 FLT) which indicates an active proliferation of tumour cells, potentially overcome by accelerated radiotherapy. A pilot study conducted in five patients with non-small cell lung cancer showed that PET/CT performed in series with 18 FDG, 18 F-miso and 18 FLT could be done almost simultaneously before and during radiotherapy [START_REF] Vera | Simultaneous positron emission tomography (PET) assessment of metabolism with ( 18 F)-fluoro-2-deoxy-D-glucose (FDG), proliferation with ( 18 F)-fluorothymidine (FLT), and hypoxia with ( 18 F)-fluoromisonidazole (F-miso) before and during radiotherapy in patients with non-small-cell lung cancer (NSCLC): a pilot study[END_REF]. A larger prospective multicentric series (79 patients) confirmed the poor prognosis of hypoxic tumours defined by 18 F-miso. In this trial, there was a significant decrease in 18 FDG and 18 F-miso during treatment, and it was demonstrated that a selective increase in the radiotherapy dose targeted at 18 F-miso-avid subvolumes was possible without increasing toxicity [START_REF] Kong | Greater reduction in midtreatment FDG-PET volume may be associated with worse survival in non-small cell lung cancer[END_REF][START_REF] Ganem | Delineation of lung cancer with FDG PET/CT during radiation therapy[END_REF].

In summary, interim 18 FDG PET/CT is a predictor of local control and survival in patients with non-small cell lung cancer. This examination is not recommended as a routine clinical procedure but recent results, to be confirmed on larger cohorts, show the interest of adaptive radiotherapy based on the results of this PET scan.

Oesophagus

Oesophageal cancers have an overall poor prognosis. Most tumours are locally advanced (grade T3 or above) at the time of diagnosis. Preoperative treatment is indicated in operable patients with locally advanced oesophageal cancer [START_REF] Van Hagen | Preoperative chemoradiotherapy for esophageal or junctional cancer[END_REF][START_REF] Lordick | Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF], this treatment allowing a complete anatomopathological response on the surgical piece for approximately 40% of patients [START_REF] Rizvi | Complete pathological response after neoadjuvant treatment in locally advanced esophageal cancer predicts long term survival: A retrospective cohort study[END_REF][START_REF] Malik | Early repeated ( 18 F)-FDG PET scans during neoadjuvant chemoradiation fail to predict histopathologic response or survival benefit in adenocarcinoma of the esophagus[END_REF]. These patients with complete anatomopathological response may thus not be treated surgically but monitored. Assessment of tumour response during initial chemoradiotherapy would identify patients with insufficient response, candidates for early surgery, and those with significant response, in whom surgery could be delayed or even avoided. However, in a study of 37 patients, the 18 FDG SUVmax variation at two weeks from the start of treatment was not sufficiently reliable to predict histopathological response (ROC accuracy: 67%), likely due to radiation-induced inflammation [START_REF] Malik | Early repeated ( 18 F)-FDG PET scans during neoadjuvant chemoradiation fail to predict histopathologic response or survival benefit in adenocarcinoma of the esophagus[END_REF]. Similarly, our team showed in 57 patients with squamous cell carcinoma that, although the uptake of 18 FDG (SUVmax), metabolic tumour volume and total lesion glycolysis decreased at 21 days in PET/CT, the tumour response at 3 months and 1 year was more effectively predicted by the parameters measured on PET/CT performed before treatment [START_REF] Palie | The predictive value of treatment response using FDG PET performed on day 21 of chemoradiotherapy in patients with oesophageal squamous cell carcinoma. A prospective, multicentre study (RTEP3)[END_REF]. This is consistent with our observation that the high uptake areas of 18 FDG in the pretreatment PET/CT indicate preferential relapse sites, these sub-volumes being a potential target for increased radiotherapy doses [START_REF] Calais | High FDG uptake areas on preradiotherapy PET/CT identify preferential sites of local relapse after chemoradiotherapy for locally advanced oesophageal cancer[END_REF].

In a meta-analysis of four studies investigating the prediction of response by interim 18 FDG PET, the overall sensitivity, specificity and odds ratio were 85%(95% CI: 76 -91), 59% (95% CI: 48 -69) and 6.82% (95% CI: 2.25 -20.72), respectively [START_REF] Cong | The predictive value of ( 18 F)-FDG PET for pathological response of primary tumor in patients with esophageal cancer during or after neoadjuvant chemoradiotherapy: a meta-analysis[END_REF]. The authors concluded that interim PET/CT should not be routinely used to guide therapeutic strategy in patients with oesophageal cancer [START_REF] Cong | The predictive value of ( 18 F)-FDG PET for pathological response of primary tumor in patients with esophageal cancer during or after neoadjuvant chemoradiotherapy: a meta-analysis[END_REF].

To date, possible therapeutic adjustments based on variations in the 18 FDG uptake during radiotherapy have not been studied in randomized trials. PET/CT during initial chemoradiotherapy for oesophageal cancer is not recommended as a routine clinical procedure.

Head and neck

Controversial results have been reported for 18 FDG PET/CT during chemoradiotherapy in patients with head and neck squamous cell carcinoma [START_REF] Farrag | Can ( 18 F)-FDG-PET response during radiotherapy be used as a predictive factor for the outcome of head and neck cancer patients?[END_REF][START_REF] Hentschel | Early FDG PET at 10 or 20 Gy under chemoradiotherapy is prognostic for locoregional control and overall survival in patients with head and neck cancer[END_REF][START_REF] Ceulemans | Can ( 18 F)-FDG-PET during radiotherapy replace post-therapy scanning for detection/demonstration of tumor response in head-and-neck cancer?[END_REF][START_REF] Castaldi | Can « early » and « late »( 18 F)-FDG PET-CT be used as prognostic factors for the clinical outcome of patients with locally advanced head and neck cancer treated with radiochemotherapy?[END_REF]. For example, in a series of 26 patients, no significant correlation was observed between changes in 18 FDG uptakes (primary tumour and lymph nodes) at 2 weeks and locoregional control, nor between the overall metabolic response and clinical outcomes [START_REF] Castaldi | Can « early » and « late »( 18 F)-FDG PET-CT be used as prognostic factors for the clinical outcome of patients with locally advanced head and neck cancer treated with radiochemotherapy?[END_REF]. In 40 other patients, the sensitivity of PET/CT at 47 Gy (week 4) was low, with the absence of a significant correlation between metabolic response and overall survival attributed to radiation-induced inflammation [START_REF] Ceulemans | Can ( 18 F)-FDG-PET during radiotherapy replace post-therapy scanning for detection/demonstration of tumor response in head-and-neck cancer?[END_REF]. On the other hand, a reduction of more than 50% in SUVmax at weeks 1 or 2 (radiotherapy dose administered between 10 and 20 Gy) was reported as a potential prognostic marker in 37 patients [START_REF] Hentschel | Early FDG PET at 10 or 20 Gy under chemoradiotherapy is prognostic for locoregional control and overall survival in patients with head and neck cancer[END_REF]. A systematic review (25 series) concluded that most studies were in favour of PET/CT to predict, during treatment, the response to chemo-radiotherapy, while highlighting its low predictive value [START_REF] Garibaldi | Interim ( 18 F)-FDG PET/CT during chemoradiation therapy in the management of head and neck cancer patients: a systematic review[END_REF].

Other radiotracers have been investigated in patients with squamous cell carcinoma of the head and neck. In a prospective study of 16 patients, three 18 F-miso PET/CT were performed at weeks 0, 2 and 5 to explore temporal changes in tumour hypoxia during chemoradiotherapy. The mean SUVmax/SUVmean of background (TBRmax) decreased significantly from 1.94 to 1.57 (week 2) and 1.27 (week 5), with this decrease being associated with better clinical outcomes [START_REF] Wiedenmann | Serial ( 18 F)fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome[END_REF]. Similar results have been reported with 18 F-fluoroazomycin arabinoside (Faza), another tracer of hypoxia [START_REF] Servagi-Vernat | A prospective clinical study of ( 18 F)-Faza PET-CT hypoxia imaging in head and neck squamous cell carcinoma before and during radiation therapy[END_REF]. In addition, changes in the uptake of 18 F-FLT were reported in advance of the tumour's volume response [START_REF] Troost | 18F-FLT PET/CT for early response monitoring and dose escalation in oropharyngeal tumors[END_REF][START_REF] Hoshikawa | Changes in ( 18 F)-fluorothymidine and ( 18 F)-fluorodeoxyglucose positron emission tomography imaging in patients with head and neck cancer treated with chemoradiotherapy[END_REF], with increased 18 F-FLT uptake after treatment associated with disease recurrence or persistence of residual tumour [START_REF] Hoshikawa | Changes in ( 18 F)-fluorothymidine and ( 18 F)-fluorodeoxyglucose positron emission tomography imaging in patients with head and neck cancer treated with chemoradiotherapy[END_REF].

In summary, the early tumour response to chemoradiotherapy of head and neck squamous cell carcinomas can be assessed by 18 FDG PET/CT at week 2 during treatment, with controversial results regarding its predictive/predictive value. It remains to be seen whether a change in therapeutic strategy based on tumour response would bring clinical benefit.

PET/CT after initial chemoradiotherapy

Initial chemoradiotherapy (neoadjuvant) is part of the standard management of locally advanced locally operable rectal and oesophageal cancers [START_REF] Lordick | Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Glynne-Jones | Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF]. Since a complete anatomopathological response is a possibility after this initial treatment, some patients may benefit from a "watch and wait" strategy rather than surgery if the tumour response is properly assessed. In addition, tumour assessment after initial chemoradiotherapy can also help to plan the surgical approach and detect a patient who has become inoperable, for example as a result of metastasis.

Rectum

For locally advanced rectal cancer, the standard approach is preoperative chemoradiotherapy followed by surgery. In the case of a complete clinical response after chemoradiotherapy, a "watch and wait" policy may be considered in patients at high risk of surgery [START_REF] Glynne-Jones | Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF]. Initial chemoradiotherapy gives a complete anatomopathological response rate of 15 to 27% in patients with locally advanced rectal cancer [START_REF] Maas | Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data[END_REF][START_REF] Joye | The role of diffusion-weighted MRI and ( 18 F)-FDG PET/CT in the prediction of pathologic complete response after radiochemotherapy for rectal cancer: a systematic review[END_REF]. "Definitive" chemoradiotherapy has become an option in the event of complete clinical remission after initial chemoradiotherapy in high-risk surgical patients, but only if the response assessment is sufficiently accurate [START_REF] Glynne-Jones | Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF]. A systematic review gathered current data on MRI with diffusion-weighted imaging (DWI) and 18 FDG PET/CT. Both MRI and PET/CT had high negative predictive values to determine complete anatomopathological response, but did not have the specificity and positive predictive values necessary to safely select patients [START_REF] Joye | The role of diffusion-weighted MRI and ( 18 F)-FDG PET/CT in the prediction of pathologic complete response after radiochemotherapy for rectal cancer: a systematic review[END_REF].

For MRI, a non-randomized study compared 129 patients followed after a complete clinical response with 228 patients who underwent surgery for an incomplete response. All patients had postchemoradiotherapy MRI to confirm their clinical response. A local relapse occurred in 44 (34%) nonoperated patients and 36 of the 41 relapses without distant disease were treated by salvage surgery. A paired analysis of surgical and non-surgical patients (109 patients in each group) reported an improvement in colostomy-free survival at 3 years in non-surgical patients (hazard ratio [HR] = 0.45, 95% CI: 0.31-0.63, p<0.0001 ; absolute difference 26%, 95% CI: 13-39). Differences in overall threeyear survival were not considered statistically significant (96%, 95% CI: 88-98 vs. 87%, 95% CI: 77-93) [START_REF] Renehan | Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis[END_REF].

Regarding PET/CT, a systematic review found that SUVmax after chemoradiotherapy was significantly associated with histological response in 6 studies. The SUV variation (ΔSUVmax as a % of baseline SUVmax) was also significantly different between response groups in seven studies,

showing that PET/CT could have a role in predicting outcome for locally advanced rectal cancers [START_REF] Memon | Systematic review of FDG-PET prediction of complete pathological response and survival in rectal cancer[END_REF].

However, to date, according to the American recommendations of NCCN 2.2019, during the evaluation after neoadjuvant chemoradiotherapy, only the thoracic CT, abdominal CT or MRI and pelvic MRI are recommended [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF], the possibility of improving results by combining PET/CT with 18 FDG, possibly in combination with MRI, has yet to be clinically demonstrated.

Oesophagus

Approximately 30% of patients with oesophageal cancer treated with neoadjuvant chemoradiotherapy do not have any residual tumours on the surgical tissue and could avoid surgery [START_REF] Van Hagen | Preoperative chemoradiotherapy for esophageal or junctional cancer[END_REF]. Non-invasive tools (CT, ultrasound endoscopy) do not accurately assess tumour response [START_REF] Swisher | Utility of PET, CT, and EUS to identify pathologic responders in esophageal cancer[END_REF]. Endoscopy with or without biopsy also does not accurately predict the histological tumour response [START_REF] Sarkaria | Post-treatment endoscopic biopsy is a poor-predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer[END_REF]. 18 FDG PET/CT was studied to identify tumours that responded to chemoradiotherapy and those that did not respond sufficiently. A meta-analysis of 6 series (out of 26 series with a total of 1,544 patients) showed that a complete PET/CT response 3 weeks after chemoradiotherapy was associated with a significant increase in overall survival and disease-free survival (HR = 0.51, 95% CI: 0.40 -0.64, p<0.00001 and 0.47, 95% CI: 0.38 -0.57, p<0.00001, respectively) [START_REF] Schollaert | A systematic review of the predictive value of ( 18 F)-FDG-PET in esophageal and esophagogastric junction cancer after neoadjuvant chemoradiation on the survival outcome stratification[END_REF]. A prospective cohort of 138 consecutive patients comparing PET/CT with endoscopy to predict complete histological response found low sensitivity (57% and 24%, respectively) and low positive predictive value (27% and 28%, respectively) [START_REF] Heneghan | Can CT-PET and endoscopic assessment post-neoadjuvant chemoradiotherapy predict residual disease in esophageal cancer?[END_REF].

In summary, 18 FDG PET/CT does not reliably identify tumours in complete response after chemoradiotherapy, but may be useful for re-evaluation after chemoradiotherapy, particularly to exclude lymphatic and blood metastases [START_REF] De Gouw | Detecting pathological complete response in esophageal cancer after neoadjuvant therapy based on imaging techniques: a diagnostic systematic review and meta-analysis[END_REF]. According to NCCN 2.2019, it is recommended between 5 and 8 weeks after the end of preoperative treatment [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF]. In case of a complete response, also present on upper gastrointestinal endoscopy with biopsy, esophagectomy (preferred in case of adenocarcinoma) or monitoring (recommendation category 2B) are recommended, with a preferred esophagectomy for patients with persistent local disease [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF].

PET/CT after exclusive chemoradiotherapy

The assessment of tumour response at the end of exclusive (chemo)radiotherapy is useful for discussing, in the event of persistent disease, possible salvage treatment or palliative treatment. The morphological response (tumour size in CT) may be several weeks or months delayed compared to changes in tracer uptake, and 18 FDG PET/CT could provide a more accurate quantification of therapeutic response than anatomical changes determined by CT [START_REF] Piessen | Ineffectiveness of ( 18 F)fluorodeoxyglucose positron emission tomography in the evaluation of tumor response after completion of neoadjuvant chemoradiation in esophageal cancer[END_REF][START_REF] Yoon | PET/CT response criteria (European Organization for Research and Treatment of Cancer) predict survival better than response evaluation criteria in solid tumors in locally advanced cervical cancer treated with chemoradiation[END_REF]. However, radiotherapy and chemotherapy can cause inflammatory changes and high diffuse accumulation of 18 FDG in the healthy tissues surrounding the tumour, producing false positive results [START_REF] Greven | Serial positron emission tomography scans following radiation therapy of patients with head and neck cancer[END_REF]. This limitation of posttherapeutic PET/CT imaging has limited its clinical use [START_REF] Yao | Clinical significance of postradiotherapy ( 18 F)-fluorodeoxyglucose positron emission tomography imaging in management of head-and-neck cancer-a long-term outcome report[END_REF]. The ideal time for the first 18 FDG PET/CT examination after radiation therapy may depend on the type of cancer. High rates of false positive and false negative results have been reported when PET/CT was acquired too soon after the end of radiotherapy [START_REF] Greven | Serial positron emission tomography scans following radiation therapy of patients with head and neck cancer[END_REF][START_REF] Amit | FDG PET/CT in monitoring response to treatment in gynecological malignancies[END_REF]. We present studies on lung, head and neck and cervical cancers.

Lung

18 F-FDG PET/CT performed at the end of chemo-radiotherapy has an important prognostic value. A prospective study evaluated its long-term prognostic value when performed 14 weeks after chemoradiotherapy in 173 patients with stage III non-small cell lung cancer. Higher tumour SUVs (SUVpeak or SUVmax) have been associated with poorer survival, although a cut-off value for clinical practice could not be established [START_REF] Machtay | Prediction of survival by ( 18 F)-fluorodeoxyglucose positron emission tomography in patients with locally advanced non-small-cell lung cancer undergoing definitive chemoradiation therapy: results of the ACRIN 6668/RTOG 0235 trial[END_REF]. A secondary analysis of SUV measured in regional lymph nodes revealed that high residual absorption after treatment was associated with a poorer local and regional response [START_REF] Markovina | Regional lymph node uptake of ( 18 F)-fluorodeoxyglucose after definitive chemoradiation therapy predicts local-regional failure of locally advanced non-small cell lung cancer: results of ACRIN 6668/RTOG 0235[END_REF].

A meta-analysis (five studies) reported that a higher SUVmax on post-therapeutic 18 18 FDG PET/CT at the end of treatment is not routinely recommended for non-small cell lung cancer according to NCCN recommendations 7.2019 [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF]. If performed, it should not be performed until at least 3 months after radiotherapy to avoid false positive results due to radiation-induced lung disease [START_REF] Choi | Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis[END_REF]. Persistent uptakes associated with radiation-induced lung disease can sometimes last 15 months after the end of treatment and justify a biopsy. Sequential and semi-quantitative 18 FDG PET/CT could be useful to distinguish radiation-induced inflammation from tumour recurrence [START_REF] Larici | Lung abnormalities at multimodality imaging after radiation therapy for non-small cell lung cancer[END_REF].

An example of the PET/CT post-therapeutic evaluation of non-small cell lung cancer treated with chemoradiotherapy is shown in Figure 2.

Head and neck

In recent decades, strategies for treating advanced head and neck squamous cell cancers have gradually shifted from surgery to radiotherapy, which is often associated with chemotherapy [START_REF] Bussink | PET-CT for response assessment and treatment adaptation in head and neck cancer[END_REF][START_REF] Argiris | Head and neck cancer[END_REF].

In a systematic review of 51 studies (2335 patients) on 18 FDG PET/CT use to assess post-treatment response, sensitivity, specificity, positive predictive value and negative predictive value for the primary site were 79.9%, 87.5%, 58.6% and 95.1%, respectively [START_REF] Gupta | Diagnostic performance of post-treatment FDG PET or FDG PET/CT imaging in head and neck cancer: a systematic review and meta-analysis[END_REF]. These estimations for the cervical lymph nodes were 72.7%, 87.6%, 52.1% and 94.5%, respectively. Tests performed more than 12 weeks after the end of final treatment had a moderately higher diagnostic accuracy [START_REF] Gupta | Diagnostic performance of post-treatment FDG PET or FDG PET/CT imaging in head and neck cancer: a systematic review and meta-analysis[END_REF].

A prospective, randomized and controlled trial analysed 564 patients with N2-N3 disease and treated with systematic neck dissection after initial chemoradiotherapy (282 patients) or neck dissection only in the event of an incomplete/equivocal response to the PET/CT performed 12 weeks after the end of chemoradiotherapy. Fewer neck dissections (54 versus 221) were performed in the PET/CT-guided surveillance group, with similar rates of surgical complications in both groups (42% and 38%, respectively). At a median follow-up of 36 months, the overall survival rate at 2 years was 85% (95% CI: 81 -89) in the monitored group and 82% (95% CI: 77 -86) in the planned surgery group [START_REF] Mehanna | PET-CT surveillance versus neck dissection in advanced head and neck cancer[END_REF]. In a prospective multicentric study including 152 patients and using a standardized analysis of 18 FDG PET/CT performed 12 weeks after chemoradiotherapy, the negative predictive value of PET/CT was 92% (95% CI: 87 -95) to predict either a negative anatomopathological result on dissection or a control after more than 12 months of follow-up [START_REF] Van Den Wyngaert | Fluorodeoxyglucose-positron emission tomography/computed tomography after concurrent chemoradiotherapy in locally advanced head-and-neck squamous cell cancer: the ECLYPS study[END_REF]. Standardized reports reduced the number of equivocal reports (15 to 3%, p=0.003) [START_REF] Van Den Wyngaert | Fluorodeoxyglucose-positron emission tomography/computed tomography after concurrent chemoradiotherapy in locally advanced head-and-neck squamous cell cancer: the ECLYPS study[END_REF].

From now on, and in particular according to the recommendations of the NCCN (3.2019), 18 FDG PET/CT performed 12 weeks after chemoradiotherapy for advanced head and neck squamous cell carcinoma is recommended in order to reduce the number of neck dissection. [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF][START_REF] Lewis-Jones | Imaging in head and neck cancer: United Kingdom National Multidisciplinary Guidelines[END_REF].

Cervix

For cervical cancer, patients with initial locoregional therapeutic failure can be treated with curative intent, hence the importance of post-therapeutic 18 FDG PET for early detection of failure [START_REF] Amit | FDG PET/CT in monitoring response to treatment in gynecological malignancies[END_REF].

In a cohort of 92 women treated with external radiation, brachytherapy and concomitant chemotherapy, 65 (70%) complete 18 FDG PET/CT responses were reported in 65 patients (70%), compared to 15 (16%) partial responses and 12 (13%) disease progression. The progression-free survival rates at 3 years were 78%, 33% and 0% respectively (p<0.001) [START_REF] Schwarz | Association of posttherapy positron emission tomography with tumor response and survival in cervical carcinoma[END_REF]. In a larger series of 328 patients from the same group, of 40 patients (12%) with a partial 18 FDG PET/CT response, 14 (35%) had no confirmed failure after a median follow-up of 35 months, 15 (38%) had an isolated local failure and 11 (28%) had a distant failure [START_REF] Schwarz | Metabolic response on post-therapy FDG-PET predicts patterns of failure after radiotherapy for cervical cancer[END_REF]. In other words, salvage surgery, if indicated for patients with partial response, would have been unnecessary for 25 patients (63%). In addition, 40 of 173 patients (23%) had tumour recurrence (34 remotely) after a complete PET/CT response and 24 of 25 patients (96%) with progressive PET/CT disease had a metastatic disease.

According to the American Society of Clinical Oncology, 18 FDG PET/CT at 3 months after chemoradiotherapy remains an option for patients at high risk of locoregional failure [START_REF] Chuang | Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline[END_REF]. In version 3.2019 of the NCCN recommendations, cervical cancer monitoring depends on the stage of the disease [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF]. For patients with stage IB3 cancer according to the International Federation of Gynaecology and Obstetrics (FIGO) or patients who have required postoperative radiotherapy or chemotherapy due to high risk factors, PET/CT performed 3 to 6 months after the end of treatment is possible [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF]. For patients with FIGO stage II-IV cancer, PET/CT (preferably) or an injected abdominal-pelvic CT scan is recommended within 3 to 6 months of the end of treatment, with pelvic MRI being optional [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF]. The role of PET/MRI remains experimental.

PET/CT during follow-up

In many cancers, 18 FDG PET/CT is considered superior or equivalent to conventional modalities for the detection of local or distant recurrences. [START_REF] Sawada | Monitoring and management of lung cancer patients following curative-intent treatment: clinical utility of 2-deoxy-2-( 18 F)-fluoro-Dglucose positron emission tomography/computed tomography[END_REF][START_REF] Kostakoglu | Early detection of recurrent disease by FDG-PET/CT leads to management changes in patients with squamous cell cancer of the head and neck[END_REF]. The three limitations illustrated in non-small cell lung cancer are valid for other cancers: 1) local inflammatory changes and fibrosis after treatment lead to false positive results and modify the specificity of the technique, 2) detection of brain metastases by PET/CT has the same limitations as in the pretherapeutic assessment, 3) additional radiation exposure and higher medical costs due to PET/CT should be taken into consideration [START_REF] Sawada | Monitoring and management of lung cancer patients following curative-intent treatment: clinical utility of 2-deoxy-2-( 18 F)-fluoro-Dglucose positron emission tomography/computed tomography[END_REF].

On the other hand, the overall strength of 18 FDG PET/CT for the follow-up appears to be its high sensitivity and high negative predictive value.

In the following paragraphs, we present the value of PET/CT for the follow-up of cancers treated conventionally by radiotherapy (lung, head and neck, oesophagus, cervix and prostate cancers) but the results of the meta-analyses presented may also include the follow-up of cancers treated by surgery and chemotherapy.

Lung

A meta-analysis of 13 studies (1035 patients) concluded that 18 FDG PET/CT was superior to conventional imaging techniques (CT, bone scan, MRI) to detect lung cancer recurrence. Sensitivity and specificity were 90% and 90% for 18 FDG PET/CT, compared to 78% and 80% for conventional imaging techniques [START_REF] He | Diagnostic efficacy of PET and PET/CT for recurrent lung cancer: a meta-analysis[END_REF]. A document review revealed changes in the management of 30 to 88% of patients followed by 18 FDG PET/CT, based on prior clinical suspicions of recurrence [START_REF] Sheikhbahaei | The value of FDG PET/CT in treatment response assessment, follow-up, and surveillance of lung cancer[END_REF]. In patients with suspected recurrence, 18 FDG PET/CT ruled out recurrence or metastasis in about one-quarter of cases [START_REF] Sheikhbahaei | The value of FDG PET/CT in treatment response assessment, follow-up, and surveillance of lung cancer[END_REF]. The absence or low 18 FDG uptake is considered a definitive indicator that there is no recurrence of lung cancer (53). 18 FDG PET/CT is not recommended according to NCCN 7.2019 for the follow-up of patients with non-small cell lung cancer [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF]. 18 FDG PET/CT may, however, be useful to study benign CT abnormalities (such as atelectasis, condensation and radiofibrosis) to differentiate them from active neoplastic disease. After radiotherapy, it is recommended to confirm histologically the suspicion of recurrence on 18 FDG PET/CT because previously irradiated areas may remain intense for up to 2 years after irradiation [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF]. In the case of stereotactic radiotherapy, the diagnosis of recurrence may be difficult because benign inflammatory/fibrotic changes may remain 18 FDG-avid for 2 years or more after treatment, emphasizing the importance of follow-up by a team experienced in such posttherapeutic effects, especially since some patients with localized recurrences after stereotactic radiotherapy may benefit from a new stereotactic surgical or radiotherapeutic treatment [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF]. 18 FDG PET/CT is interesting for detecting recurrences accessible for curative surgery in the event of local-regional recurrence, second primary cancer or oligometastatic disease [START_REF] Leeman | Patterns of treatment failure and postrecurrence outcomes among patients with locally advanced head and neck squamous cell carcinoma after chemoradiotherapy using modern radiation techniques[END_REF].

Head and neck

The performance of 18 FDG PET/CT in detecting early recurrence or second primary cancer was compared retrospectively to a neck CT and physical examination/endoscopy in 99 patients.

Sensitivity, specificity, positive and negative predictive values for detection of local and regional recurrence, remote recurrence and a second primary cancer were 100%, 87%, 57% and 100%, respectively, for 18 FDG PET/CT, compared to 62%, 95%, 67% and 94%, respectively, for neck CT and 23%, 99%, 75% and 89%, respectively, for physical examination/endoscopy [START_REF] Kostakoglu | Early detection of recurrent disease by FDG-PET/CT leads to management changes in patients with squamous cell cancer of the head and neck[END_REF]. In 19 patients with positive 18 FDG PET/CT results, a significant change in disease management occurred, resulting in either salvage or systemic treatment [START_REF] Kostakoglu | Early detection of recurrent disease by FDG-PET/CT leads to management changes in patients with squamous cell cancer of the head and neck[END_REF].

A meta-analysis of 23 studies (2247 PET/CT) reported overall sensitivity and specificity of 92% and 87% respectively for recurrence detection [START_REF] Sheikhbahaei | Diagnostic accuracy of follow-up FDG PET or PET/CT in patients with head and neck cancer after definitive treatment: a systematic review and meta-analysis[END_REF]. It has been suggested to combine early (12 weeks after chemoradiotherapy) and late (at 1 year) PET/CT to improve detection of recurrences [START_REF] Van Den Wyngaert | Fluorodeoxyglucose-positron emission tomography/computed tomography after concurrent chemoradiotherapy in locally advanced head-and-neck squamous cell cancer: the ECLYPS study[END_REF].

However, if 18 FDG PET/CT is recognized as potentially useful in the event of a suspicion this examination is not recommended for systematic monitoring (69).

Oesophagus

Survival after a recurrence of oesophageal cancer is low [START_REF] Parry | Prognosis and treatment after diagnosis of recurrent esophageal carcinoma following esophagectomy with curative intent[END_REF]. In a meta-analysis of eight studies (486 patients), the combined sensitivity and specificity of 18 FDG PET/CT for the diagnosis of recurrence were 96% and 78% respectively [START_REF] Goense | Diagnostic performance of ( 18 F)-FDG PET and PET/CT for the detection of recurrent esophageal cancer after treatment with curative intent: a systematic review and meta-analysis[END_REF]. The high false positive rate justifies histopathological confirmation of the suspected recurrence of 18 FDG (71).

According to NCCN 2.2019 recommendations, for patients with T1b cancer treated with chemoradiotherapy, in addition to endoscopic follow-up, imaging follow-up (injected thoracoabdominal CT or 18 FDG PET/CT) should be considered every 6 to 9 months for the first two years and annually for up to 5 years. PET/CT is not indicated in the follow-up of other patients [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF].

Cervix

Many systematic reviews and meta-analyses have been published concerning the diagnostic value of 18 FDG PET(/CT) to diagnose cervical cancer recurrence [START_REF] Chu | Diagnostic value of ( 18 F)-FDG-PET or PET-CT in recurrent cervical cancer: a systematic review and meta-analysis[END_REF][START_REF] Meads | Evaluating PET-CT in the detection and management of recurrent cervical cancer: systematic reviews of diagnostic accuracy and subjective elicitation[END_REF][START_REF] Ding | Diagnosis of recurrent uterine cervical cancer: PET versus PET/CT: a systematic review and meta-analysis[END_REF][START_REF] Xiao | Positron emission tomography alone, positron emission tomography-computed tomography and computed tomography in diagnosing recurrent cervical carcinoma: a systematic review and meta-analysis[END_REF][START_REF] Auguste | Evaluating PET-CT in routine surveillance and follow-up after treatment for cervical cancer: a cost-effectiveness analysis[END_REF]. Good sensitivity and specificity have been reported for 18 FDG PET with or without CT, as the accuracy of CT is limited to detect recurrent cervical cancer [START_REF] Auguste | Evaluating PET-CT in routine surveillance and follow-up after treatment for cervical cancer: a cost-effectiveness analysis[END_REF]. For example, the pooled sensitivity and specificity of 18 FDG PET to detect locoregional recurrence were 82% and 98% respectively [START_REF] Chu | Diagnostic value of ( 18 F)-FDG-PET or PET-CT in recurrent cervical cancer: a systematic review and meta-analysis[END_REF].

However, the addition of 18 FDG PET/CT for routine surveillance (clinical examination, CT, MRI) has been evaluated as more costly with only a minimal increase in efficacy, including in women with persistent and recurrent cervical cancer. The use of 18 FDG PET/CT for systematic surveillance has thus been criticized [START_REF] Meads | Positron emission tomography/computerised tomography imaging in detecting and managing recurrent cervical cancer: systematic review of evidence, elicitation of subjective probabilities and economic modelling[END_REF][START_REF] Meads | Evaluating PET-CT in the detection and management of recurrent cervical cancer: systematic reviews of diagnostic accuracy and subjective elicitation[END_REF][START_REF] Auguste | Evaluating PET-CT in routine surveillance and follow-up after treatment for cervical cancer: a cost-effectiveness analysis[END_REF], and the use of imaging, including PET/CT, for surveillance is limited and reserved for exploration in the event of symptoms or abnormalities on clinical examination [START_REF] Salani | An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations[END_REF]. NCCN (version 5.2019) recommends PET/CT to be performed if there is a suspicion of recurrence or metastasis and pelvic MRI also be considered in this case [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF].

Prostate

18 FDG PET/CT plays a very limited role in prostate cancer patients, including in the localization of the disease in patients with biochemical failure after treatment [START_REF] Jadvar | Positron emission tomography in prostate cancer: summary of systematic reviews and meta-analysis[END_REF]. PET/CT with radiolabelled acetate and radiolabelled choline can explore prostate cancer, with the majority of studies using radiolabelled choline [START_REF] Evangelista | Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis[END_REF]. Choline can carry a radioelement 11 C (half-life 20 minutes) or 18 F (half-life 110 minutes).

The physiological biodistributions of 11 C-choline and 18 F-fluorocholine are generally similar, with the exception of the lower excretion of the renal tracer of 11 C-choline (reduced accumulation in the bladder) [START_REF] Evangelista | Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis[END_REF].

A meta-analysis (19 studies, 1555 patients) of PET/CT with radiolabelled choline in patients with biochemical relapse reported overall sensitivity and specificity of 86% and 93% for all disease sites (prostatic bed, lymph nodes and bones), 75% and 82% for prostate recurrence, 100% and 82% for ganglion metastases [START_REF] Treglia | Relationship between prostatespecific antigen kinetics and detection rate of radiolabelled choline PET/CT in restaging prostate cancer patients: a meta-analysis[END_REF].

The diagnostic performance of choline PET/CT depends on serum prostate specific antigen levels and kinetics. In a systematic review of 14 articles, the overall combined detection rate of choline PET/CT was 58%, increasing to 65% when the serum prostate specific antigen concentration doubling time was 6 months or less, to 71% when the serum prostate specific antigen concentration increase kinetics was more than 1 ng/mL per year and 77% when it was more than 2 ng/mL per year [START_REF] Nanni | 18 F)-FACBC (anti1amino-3-( 18 F)-fluorocyclobutane-1-carboxylic acid) versus ( 11 C)-choline PET/CT in prostate cancer relapse: results of a prospective trial[END_REF].

Another radiotracer, 18 F-fluciclovin, has results comparable to choline PET with an 85% match [START_REF] Afshar-Oromieh | Diagnostic performance of 68Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 patients[END_REF].

New tracers are under development, but they are not yet fully approved by the regulatory authorities (French or American), are not readily available and are considered experimental products at this time. For example, imaging of prostate specific membrane antigen using gallium-68 can provide better detection of recurrences at lower serum prostate specific antigen levels with comparable sensitivity and specificity and better detection rates [START_REF] Afshar-Oromieh | Diagnostic performance of 68Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 patients[END_REF][START_REF] Calais | 18 F)-fluciclovine PET-CT and ( 68 Ga)-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial[END_REF].

According to the recommendations of NCCN 4.2019, the use of PET/CT or PET/MRI with choline or fluciclovin may be used in cases of biochemical recurrence to detect small volumes of the disease in soft tissue or bone, with histological confirmation recommended taking into account the risk of false positive [START_REF]NCCN -Evidence-Based Cancer Guidelines[END_REF]. Indeed, it has been demonstrated the value of localized treatment in case of oligoprogression.

Conclusion

We have seen in this review that, in many cancers, PET/CT is potentially useful for interim evaluation during radiotherapy, at the end of neo-adjuvant radiotherapy, at the end of final treatment or during follow-up. Table 1 is a summary table of the usefulness of the indications.

Despite this usefulness, cost-effectiveness must generally be taken into account before deciding to perform a PET/CT scan. In addition, greater standardization of evaluation parameters must be achieved. If combined PET/MRI has been evaluated only to a limited extent in this area, it is hoped that the two techniques will have a synergistic effect for a better therapeutic evaluation. Finally, the recommendations in this field evolve regularly and require regular updating.

Figure 1 .

 1 Figure 1. Illustration of the different possible timings of positron emission tomography combined with computed tomography for the evaluation of (chemo)radiotherapy.

Figure 2 .

 2 Figure 2. Benefits of positron emission tomography scans for the evaluation of radiotherapy: example of examination of a patient with bronchial adenocarcinoma treated by chemoradiation. a: ( 18 F)-FDG PET/CT performed before treatment (yellow arrow: bronchial adenocarcinoma); b: ( 18 F)-FDG PET/CT performed 3 months after chemoradiotherapy (red arrow: appearance of a post-radiation inflammation); c: ( 18 F)-FDG PET/CT performed 9 months after chemoradiotherapy (green arrow: regression of pulmonary uptake confirming the post-radiation inflammation, orange arrow: appearance of a right lower lobar nodule with uptake, in favour of metastasis). PET/CT: positron emission tomography combined with computed tomography; FDG: fluorodeoxyglucose.

Table 1 .

 1 Summary of the different recommendations of the National Comprehensive Cancer Network (NCCN) for the use of positron emission tomography combined with computed tomography in the evaluation of radiotherapy according to the timing and the type of cancer. Rectal cancer PET/CT not recommended. To date, the panel recommends chest CT, abdominal CT or MRI and pelvic MRI for restaging 2.2019 Oesophageal cancer 18 FDG PET/CT is useful for detecting distant lymph node or blood metastases. Must be done at least 5 to 8 weeks after the end of preoperative treatment. Endoscopy and upper gastrointestinal tract biopsy are also recommended. Oesophagectomy (preferably for In case of a clinical response, a 18 FDG PET/CT is recommended at least 12 weeks with, in case of positivity, a CT or MRI scan. Not recommended for clinical routine. However, many benign conditions (such as atelectasis, condensation and radiofibrosis) are difficult to differentiate from active neoplastic CT disease and 18 FDG PET/CT can be used in these settings. In case of positive PET, histopathological confirmation of disease recurrence must be performed (risk of false positive with areas already treated with radiotherapy that may remain avid for FDG for up to 2 years) CT or PET/MRI with ( 11 C)-choline or ( 18 F)fluciclovin PET/CT (in France, [ 11 C-]choline is replaced by [ 18 F]choline), especially in the case of bone scans with equivocal results (PET/CT or PET/MRI with [ 18 F]-Na can also be considered

	Examination	Recommendation
	time/type of cancer

CT: computed tomography; FDG: fluorodeoxyglucose; FIGO: International Federation of Gynaecology and Obstetrics; MRI: magnetic resonance imaging; PET: positron emission tomography.

Author contribution

PD: conceptualization, data curation, writing -original draft; ST: writing -review and editing; RM, PB: resources; MDM: data curation, visualization; PV: conceptualization, supervision, writingreview and editing.