FDG-PET/CT during concomitant chemo radiotherapy for esophageal cancer: Reducing target volumes to deliver higher radiotherapy doses.

Abstract Background. A planning study investigated whether reduced target volumes defined on FDG-PET/CT during radiotherapy allow total dose escalation without compromising normal tissue tolerance in patients with esophageal cancer. Material and methods. Ten patients with esophageal squamous cell carcinoma (SCC), candidate to curative-intent concomitant chemo-radiotherapy (CRT), had FDG-PET/CT performed in treatment position, before and during (Day 21) radiotherapy (RT). Four planning scenarios were investigated: 1) 50 Gy total dose with target volumes defined on pre-RT FDG-PET/CT; 2) 50 Gy with boost target volume defined on FDG-PET/CT during RT; 3) 66 Gy with target volumes from pre-RT FDG-PET/CT; and 4) 66 Gy with boost target volume from during-RT FDG-PET/CT. Results. The median metabolic target volume decreased from 12.9 cm3 (minimum 3.7–maximum 44.8) to 5.0 cm3 (1.7–13.5) (p = 0.01) between pre- and during-RCT FDG-PET/CT. The median PTV66 was smaller on during-RT than on baseline FDG-PET/CT [108 cm3 (62.5–194) vs. 156 cm3 (68.8–251), p = 0.02]. When total dose was set to 50 Gy, planning on during-RT FDG-PET/CT was associated with a marginal reduction in normal tissues irradiation. When total dose was increased to 66 Gy, planning on during-RT PET yielded significantly lower doses to the spinal cord [Dmax = 44.1Gy (40.8–44.9) vs. 44.7Gy (41.5–45.0), p = 0.007] and reduced lung exposure [V20Gy = 23.2% (17.3–27) vs. 26.8% (19.7–30.2), p = 0.006]. Conclusion. This planning study suggests that adaptive RT based on target volume reduction assessed on FDG-PET/CT during treatment could facilitate dose escalation up to 66 Gy in patients with esophageal SCC.

The survival probability of esophageal cancer patients remains disappointing [1]. The overall survival is low. Squamous cell carcinoma (SCC) is the most frequent histological type but rising incidences of adenocarcinomas have been reported elsewhere in the world [1]. Chemoradiotherapy (CRT) is the standard treatment of locally advanced or inoperable SCC [1,2]. The proximity of healthy organs often limits the radiotherapy (RT) dose that can be delivered without excessive toxicity [3], possibly hampering tumor control. In 2002, a single randomized trial (INT0123/RTOG94-05) [4] failed to demonstrate a benefi t of escalating RT dose from 50.4 to 64.8 Gy using non-conformal RT planning but these date are contradicted by others studies [5]. Since then, the progress in medical imaging (FDG-PET/CT) and RT technique has renewed the interest in dose escalation for esophageal cancer.
Imaging modalities investigating tumor response during CRT are expected to facilitate RT plan adaptation. In case of tumor response, reduced target volumes could receive higher total doses without compromising normal tissue tolerance [6]. FDG-PET/CT is superior to CT scanner to identify the tumor volume in esophageal cancer [7]. When performed during CRT, FDG-PET/CT aims at assessing treatment-induced variations in anatomical and functional tumor volumes that could be used to reduce the RT target volume. In a prospective series [8], 57 patients with esophageal SCC underwent FDG-PET/CT before and during (Day 21) CRT (RTEP3 study, N ° NCT 00934505, http://register. clinicaltrials.gov). The functional tumor volumes were smaller at Day 21 of CRT than at baseline FDG-PET/CT [geometric mean (95% confi dence limits): 6.5 cm 3 (4.7 -9.1) vs. 12.8 (9.9 -16.7), respectively, p Ͻ 10 Ϫ 4 ]. The patients with high FDG uptake during RCT had a poor outcome.
As an ancillary study to RTEP3, we have investigated whether FDG-PET/CT during CRT would help to plan total doses up to 66 Gy while reducing lung and spinal cord irradiation. We present the results of a planning study performed on a subgroup of 10 patients with FDG-PET/CT acquired in treatment position before and during CRT.
For the present study, we selected a subgroup of patients who underwent FDG PET/CT in treatment position (arms above head for intra-thoracic tumors or along the trunk for cervical tumors, arm or head support depending on arm position, and strict alignment on midline and lateral skin tattoos with laser beams).

FDG-PET/CT imaging
FDG-PET/CT images were acquired while free breathing, at baseline (t0) within 15 days before CRT (PET 1 ) and at Day 21 ( Ϯ 3 days) during CRT (PET 2 , see Supplementary Figure 1, to be found online at http://informahealthcare.com/doi/abs/10.3 109/0284186X.2014.973062). The CT scan data were used for attenuation correction and anatomic localization. For each patient, the two FDG-PET/ CT were performed on the same machine and under the same acquisition and reconstruction conditions: patients fasting for at least 6 hours, blood-glucose level measured before each FDG-PET/CT, 4.5 MBq/ kg of 18 FDG injected intra-venously, after a rest of at least 20 minutes, start of acquisition 60 Ϯ 10 minutes post-injection. PET 2 acquisition had to be done after the same post-injection interval ( Ϯ 5 minutes) as for PET 1 . All PET images were reconstructed using Fourier Rebinning (FORE) and Attenuation Weighted Ordered Subset Expectation Maximization (AWOSEM) algorithm, corrected for random coincidences, scatter and attenuation using the CT scan data, and smoothed with a Gaussian fi lter (full width at half maximum ϭ 5 mm).
In the present work, a SUV threshold was chosen by two experienced physicians (1 radiation oncologist, 1 nuclear medicine physician) after visual inspection of the region of interest (ROI) and defi ned an optimal standard uptake value (SUV) threshold (Leonardo workstation, Siemens Medical Solutions, Hoffman Estates, Knoxville, TN, USA). This process allowed excluding FDG uptake due to treatmentinduced esophagitis. This approach was used on a larger series of 66 consecutive patients imaged in our institution [10]. The concordance between investigators was validated on a subset of 26 patients. Our 10 patients were abstracted from this series according to the following criteria: 1) inclusion in the RTEP3 prospective study; and 2) FDG PET/CT acquisition in RT position. One should note that such an approach requires strict quality insurance to obtain: 1) comparable SUV values (i.e. standardization of the acquisition process); and 2) reliable coregistration of sequential acquisitions (i.e. PET/CT in treatment position). In a second time, CT 1 and CT 2 were automatically registered on vertebrae (with manual adjustment if necessary) so that the delineated volumes could be superimposed and transferred to the RT planning workstation.
The FDG uptake volumes delineated on PETs were considered as gross tumor volume (GTV PET ). Primary tumor and positive mediastinal lymph nodes were labeled as GTV tPETn and GTV nPETn respectively, n being either 1 (PET 1 at baseline) or 2 (PET 2 at Day 21 during CRT). The GTV PET included the primary tumor (GTV tPET ) and the nodes (GTV nPET ) delineated on the same PET. SUV max were measured in each GTV PET . The nodes with small diameter Ͼ 1 cm on CT were included in the GTV.
To account for microscopic disease extension, a clinical target volume (CTV) was defi ned by adding a 5-cm cranio-caudal margin to the GTV PET , then manually excluding the anatomical barriers (lung, trachea, large vessels, bones and heart) when not involved. Any mediastinal lymph node station containing nodal GTV or with a risk of invasion Ն 20% was delineated as part of the CTV. This CTV was to receive 40 Gy (CTV40) in all plans.
Four different plans (i.e. scenarios) were calculated for each patient: Plan 1: 50-Gy total dose to a CTV50 extend-1) ing 2 cm superiorly and inferiorly from GTVt PET1 excluding the anatomical barriers, plus the lymphnode stations with FDG uptake at PET 1 , Plan 2: 50-Gy total dose to a CTV50 extend-2) ing 2 cm superiorly and inferiorly from GTVt PET2 excluding the anatomical barriers, plus the lymphnode stations with FDG uptake at PET 2 , Plan 3: 66 Gy to a CTV66 with the same 3) cranio-caudal margins around the GTVt PET1 and a 5-mm isotropic margin around FDG positive lymphnodes at PET 1 (manually edited to exclude anatomical barriers). Plan 4: 66 Gy to a CTV66 with the same 4) cranio-caudal margins around the GTVt PET2 and a 5-mm isotropic margin around FDG positive lymphnodes at PET 2 (manually edited to exclude anatomical barriers).

Planning
The plans were based on four beams conformed on Beam ' s Eye Views to the sequential PTVs. Eighteen MV X beams were used, except for cervical tumors where 6MV X rays were allowed if necessary. The doses were calculated using an ECLIPSE treatment planning system (VARIAN ® v10.0) without heterogeneity correction. The doses to the PTVs were prescribed at the isocenter. The objectives for PTV doses were minimal and maximum doses between 95% and 107% of the prescribed dose, and 95% of the PTV included in the 95% isodose curve. To compare the four scenarios, we used the doses received by 98%, 50% and 2% of the PTVs, respectively termed as D98, D50 and D2. The constraints for the organs at risk (OAR) were: lungs: V 20Gy Ͻ 27% and V 30Gy Ͻ 20% of the total lung volume (including the PTVs); spinal cord: maximum dose Ͻ 45Gy; heart: V 40Gy Ͻ 30%; liver: V 30Gy Ͻ 40%; kidneys: V 20Gy Ͻ 25%.
The baseline FDG-PET/CT (PET 1 ) was performed at a median time interval of 14 days (range 3 -42 days) before the start of RCT and PET 2 at median Day 21 (range 18 -23 days) of RCT.

Statistical analysis
The objective was to investigate whether the target volumes could be irradiated to either 50 Gy (plans 1 and 2) or 66 Gy (plans 3 and 4). The parameters (D max , V dose ) describing the OARs ' dose distributions were compared using a non-parametric test for quantitative variables (Wilcoxon signed-rank test for difference in medians with approximation for continuity correction, NCSS 2007 version 07.1.18, Kaysville, UT, USA). A difference was considered as statistically signifi cant if p Ͻ 0.05 (two-sided tests).

Results
All patients had a signifi cant FDG uptake on PET 2 . The GTV PET2 could not be reliably delineated in three patients (#10, #47 and #54) with acute esophagitis on PET during RT. In the 10 remaining patients, the median GTV PET decreased from 12.9 cm 3 (minimum 3.7 -maximum 44.8) to 5.0 cm 3 (1.7 -13.5) (p ϭ 0.01) between PET 1 and PET 2 (Supplementary Table I  The comparison of the four different PTVs is shown on Figure 1. The differences between the median volumes of PTV 50-1 and PTV 50-2 were close to statistical signifi cance [215 cm 3 (102 -459) vs. 182 cm 3 (94.4 -343) at PET 1 and PET 2 , respectively, p ϭ 0.053]. The PTV 66 was smaller on PET 2 than on PET 1 [156 cm 3 (68.8 -251) vs. 108 cm 3 (62.5 -194), p ϭ 0.02]. Table I shows the comparisons between scenarios 1 and 2, i.e. when planning a total dose of 50 Gy in the PTV 50 . No signifi cant differences were observed in the respective PTVs ' coverage. Planning on PET 2 was associated with a signifi cant reduction in lung V 20 , although the absolute gain was small [-0.15% ( Ϫ 1.1 -0.1), p ϭ 0.03]. The reduction in lung V30 was close to signifi cance (p ϭ 0.0503). Large absolute benefi ts in heart V40, liver V30 and esophagus D Max were observed occasionally, although statistical signifi cance was not reached.

Discussion
The present planning study was conducted on 10 pairs of pre-and during-RCT FDG-PET/CT out of 57 patients with esophageal SCC included in a prospective study on the prognostic value of FDG-PET/ CT during CRT [8]. This is the fi rst report investigating adaptive planning taking into account tumor metabolic response at Day 21 of CRT. The total RT dose could be increased from 50 to 66 Gy while signifi cantly reducing normal tissue exposure. When the dose was left to 50 Gy, the benefi t of replanning on PET during CRT did not reached statistical signifi cance in terms of OARs ' dose distribution. Further clinical studies are necessary to evaluate whether there is any benefi t of this approach in terms of local control and survival.
The analysis of the whole RTEP3 study group demonstrated that the functional tumor volumes measured on FDG-PET/CT at Day 21 of CRT were signifi cantly smaller than on baseline PET/CT [8]. This observation prompted us to investigate whether tumor response could yield improved dose distributions after replanning, adapting the RT technique to the reduced target volumes. The patients having had their FDG PET/CT acquired in treatment position were selected for reliable image sets registration and  The different steps of the study were conducted in a single center by the same team (radiation oncologists, nuclear medicine physicians, medical physicists). The target volumes and OAR delineation procedures, as well as the planning objectives and dose/volume constraints were those for daily use in our department and recommended for centers participating in the CONCORDE prospective trial (see below). Contrasting with the large reduction in PTV on PET 2 , the median reduction in OAR irradiation was moderate, although statistically signifi cant when increasing total dose to 66 Gy. Larger benefi ts were reported with IMRT [6,11 -13]. For instance, Kole et al. [12] compared the plans obtained with 3D- RT and IMRT to deliver 50.4  FDG-PET/CT has an established role in the diagnosis and staging of esophageal cancer [14], although its use for RT planning is still debated [15]. As for the detection of metastatic mediastinal lymph nodes, the sensitivity ranges between 30% and 93% and the specifi city between 79% and 100% [15]. We included in the GTV the nodes with small diameter Ͼ 1 cm on CT to avoid the potential consequences of false negative FGD-PET/CTs [16]. As for the primary tumor, the delineation on a sole planning CT has been criticized [15,16]. However, no standard method has yet been accepted to delineate the primary tumor on FDG-PET/CT. When comparing tumor lengths as measured on FDG-PET/CT and on pathological specimens, fi xed SUV threshold values of 2.5 [17] or 1.4 [18] have been proposed, although CT and FDG PET/CT appeared to be complementary. In non-small cell lung cancer (NSCLC), when delineating a tumor volume during RT or CRT, the manually drawn volumes seemed to be more reliable than the volumes delineated by automatic or semi-automatic methods [19].
Relatively high (around 50% in the CROSS trial [20] pathological response rates have been reported after moderate doses of RT [20,21]. However, several arguments support the potential of increased RT dose in esophageal cancer. Several randomized trials reported local-relapse rates around 40 -50% after RCT alone [4,22] while 90% of the local relapses occurred in the GTV in a retrospective series [4]. Randomized trials comparing RCT alone versus RCT plus surgery demonstrated that surgery improved loco-regional control, although not associated to increased overall survival probability [22]. our sample, we could not identify these patients. In the CONCORDE trial, FDG-PET/CT will be repeated around 50 Gy, hopefully providing new data to assess the prognostic/predictive value of FDG-PET/CT and its role in the determination of RT target volumes. In the mean time, FDG-PET/CT during RCT for esophageal cancer should be considered as investigational.
In summary, FDG-PET/CT performed at Day 21 of CRT for esophageal cancer shows a decrease in metabolic tumor volume. Our planning study indicates that adapting the target volumes on the basis of FDG-PET/CT images acquired during treatment could facilitate an increase in total RT dose within the routine frame of normal tissues dose/volumes constraints, associated to better sparing of the spinal cord and lungs.

Declaration of interest:
The authors thank David Voisard (radiation oncology and Medical Physics, Henri Becquerel Center) for his help in developing this article. The authors report no confl icts of interest. The authors alone are responsible for the content and writing of the paper.
This suggests that a more intensive treatment (i.e. RCT plus surgery or escalated RT dose) would improve loco-regional control. In a single randomized trial (INT0123/RTOG94-05) [4], 218 patients received concomitant CRT and RT doses of either 64.8 Gy or 50.4 Gy. After a median follow-up duration of 29.5 months in surviving patients, no significant benefi t of higher RT doses was observed in terms of overall survival or local/regional control. The trial was opened in 1995 and closed in 1999, so that treatment planning was based on classical simulator fi elds. It may well be assumed that conformal techniques based on planning CT (and more recently on FDG-PET/CT) would have achieved a more accurate coverage of the target volumes [6]. In NSCLC patients, two phase I -II studies have suggested a benefi t of higher RT doses [23,24]. The increased dose levels were selected so that lung tolerance would not be impaired. Smaller tumors, i.e. situations where lung exposure was already limited, received higher doses. Therefore, the reported correlations between higher doses and better control rates may also refl ect a spurious link between total dose and tumor size. Combined analyses of head and neck cancers in retrospective series were consistent with a 2% increase in tumor control when RT dose is increased by 1% [25]. The clinical demonstration requires both accurate dosimetry and delivery (not achieved according to nowadays criteria in the INT 0123) and a population of tumors that are homogeneous regarding their radiosensitivity [25]. The ongoing efforts with IMRT [8,15 -18,20], IMRT with protons, along with the CONCORDE trial, demonstrate that dose escalation in esophageal cancer is still a domain of active clinical research.
The adaptive strategy presented here deserves more investigation before FDG-PET/CT during CRT can be implemented in routine. Kwee et al. [21] reported sensitivity and specifi city values ranging from 33% to 100% and from 30% to 100%, respectively, when FDG PET/CT was used to predict pathological response to RCT. Technically speaking, the low resolution of PET images, possibly results in apparent response while viable tumors cells still exist. A counter argument is that those viable cells could be much less numerous in areas associated to reduced FDG uptake, therefore requiring less RT total dose. These areas are likely to lie in the vicinity of the residual volume and to be included in the CTV for dose increase (5 mm lateral/2 cm cranio-caudal margins in the present study).
Although statistically signifi cant, the median reduction in dose to the OARs may be considered as making limited clinical sense. Our data suggest that not all patients would benefi t from replanning on FDG-PET/CT during RT. Given the limited size of