Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. METHODS: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by 18F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (18F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333. FINDINGS: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the 18F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the 18F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the 18F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the 18F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13). INTERPRETATION: 18F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

IMRT and 3D conformal radiotherapy with or without elective nodal irradiation in locally advanced NSCLC: A direct comparison of PET-based treatment planning.

AIM: The potential of intensity-modulated radiation therapy (IMRT) as opposed to three-dimensional conformal radiotherapy (3D-CRT) is analyzed for two different concepts of fluorodeoxyglucose positron emission tomography (FDG PET)-based target volume delineation in locally advanced non-small cell lung cancer (LA-NSCLC): involved-field radiotherapy (IF-RT) vs. elective nodal irradiation (ENI). METHODS: Treatment planning was performed for 41 patients with LA-NSCLC, using four different planning approaches (3D-CRT-IF, 3D-CRT-ENI, IMRT-IF, IMRT-ENI). ENI included a boost irradiation after 50 Gy. For each plan, maximum dose escalation was calculated based on prespecified normal tissue constraints. The maximum prescription dose (PD), tumor control probability (TCP), conformal indices (CI), and normal tissue complication probabilities (NTCP) were analyzed. RESULTS: IMRT resulted in statistically significant higher prescription doses for both target volume concepts as compared with 3D-CRT (ENI: 68.4 vs. 60.9 Gy, p < 0.001; IF: 74.3 vs. 70.1 Gy, p < 0.03). With IMRT-IF, a PD of at least 66 Gy was achieved for 95 % of all plans. For IF as compared with ENI, there was a considerable theoretical increase in TCP (IMRT: 27.3 vs. 17.7 %, p < 0.00001; 3D-CRT: 20.2 vs. 9.9 %, p < 0.00001). The esophageal NTCP showed a particularly good sparing with IMRT vs. 3D-CRT (ENI: 12.3 vs. 30.9 % p < 0.0001; IF: 15.9 vs. 24.1 %; p < 0.001). CONCLUSION: The IMRT technique and IF target volume delineation allow a significant dose escalation and an increase in TCP. IMRT results in an improved sparing of OARs as compared with 3D-CRT at equivalent dose levels.

Commissioning and first clinical application of mARC treatment.

BACKGROUND: The modulated arc (mARC) technique has recently been introduced for Siemens ARTISTE linear accelerators. We present the first experiences with the commissioning of the system and first patient treatments. PATIENTS AND METHODS: Treatment planning and delivery are presented for the Prowess Panther treatment planning system or, alternatively, an in-house code. Dosimetric verification is performed both by point dose measurements and in 3D dose distribution. RESULTS: Depending on the target volume, one or two arcs can be used to create highly conformal plans. Dosimetric verification of the converted mARC plans with step-and-shoot plans shows deviations below 1 % in absolute point dose; in the 3D dose distribution, over 95 % of the points pass the 3D gamma criteria (3 % deviation in local dose and 3 mm distance to agreement for doses > 20 % of the maximum). Patient specific verification of the mARC dose distribution with the calculations has a similar pass rate. Treatment times range between 2 and 5 min for a single arc. CONCLUSIONS: To our knowledge, this is the first report of clinical application of the mARC technique. The mARC offers the possibility to save significant amounts of time, with single-arc treatments of only a few minutes achieving comparable dose distribution to IMRT plans taking up to twice as long.

PET-based delineation of tumour volumes in lung cancer: comparison with pathological findings.

PURPOSE: The objective of the study was to validate an adaptive, contrast-oriented thresholding algorithm (COA) for tumour delineation in (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for non-small cell lung cancer (NSCLC) in comparison with pathological findings. The impact of tumour localization, tumour size and uptake heterogeneity on PET delineation results was also investigated. METHODS: PET tumour delineation by COA was compared with both CT delineation and pathological findings in 15 patients to investigate its validity. Correlations between anatomical volume, metabolic volume and the pathology reference as well as between the corresponding maximal diameters were determined. Differences between PET delineations and pathological results were investigated with respect to tumour localization and uptake heterogeneity. RESULTS: The delineated volumes and maximal diameters measured on PET and CT images significantly correlated with the pathology reference (both r > 0.95, p < 0.0001). Both PET and CT contours resulted in overestimation of the pathological volume (PET 32.5 ± 26.5%, CT 46.6 ± 27.4%). CT volumes were larger than those delineated on PET images (CT 60.6 ± 86.3 ml, PET 48.3 ± 61.7 ml). Maximal tumour diameters were similar for PET and CT (51.4 ± 19.8 mm for CT versus 53.4 ± 19.1 mm for PET), slightly overestimating the pathological reference (mean difference CT 4.3 ± 3.2 mm, PET 6.2 ± 5.1 mm). PET volumes of lung tumours located in the lower lobe were significantly different from those determined from pathology (p = 0.037), whereas no significant differences were observed for tumours located in the upper lobe (p = 0.066). Only minor correlation was found between pathological tumour size and PET heterogeneity (r = -0.24). CONCLUSION: PET tumour delineation by COA showed a good correlation with pathological findings. Tumour localization had an influence on PET delineation results. The impact of tracer uptake heterogeneity on PET delineation should be considered carefully and individually in each patient. Altogether, PET tumour delineation by COA for NSCLC patients is feasible and reliable with the potential for routine clinical application.

Cardiac Function Modifies the Impact of Heart Base Dose on Survival: A Voxel-Wise Analysis of Patients With Lung Cancer From the PET-Plan Trial.

INTRODUCTION: Heart dose has emerged as an independent predictor of overall survival in patients with NSCLC treated with radiotherapy. Several studies have identified the base of the heart as a region of enhanced dose sensitivity and a potential target for cardiac sparing. We present a dosimetric analysis of overall survival in the multicenter, randomized PET-Plan trial (NCT00697333) and for the first time include left ventricular ejection fraction (EF) at baseline as a metric of cardiac function. METHODS: A total of 205 patients with inoperable stage II or III NSCLC treated with 60 to 72 Gy in 2 Gy fractions were included in this study. A voxel-wise image-based data mining methodology was used to identify anatomical regions where higher dose was significantly associated with worse overall survival. Univariable and multivariable Cox proportional hazards models tested the association of survival with dose to the identified region, established prognostic factors, and baseline cardiac function. RESULTS: A total of 172 patients remained after processing and censoring for follow-up. At 2-years posttreatment, a highly significant region was identified within the base of the heart (p < 0.005), centered on the origin of the left coronary artery and the region of the atrioventricular node. In multivariable analysis, the number of positron emission tomography-positive nodes (p = 0.02, hazard ratio = 1.13, 95% confidence interval: 1.02-1.25) and mean dose to the cardiac subregion (p = 0.02, hazard ratio = 1.11 Gy-1, 95% confidence interval: 1.02-1.21) were significantly associated with overall survival. There was a significant interaction between EF and region dose (p = 0.04) for survival, with contrast plots revealing a larger effect of region dose on survival in patients with lower EF values. CONCLUSIONS: This work validates previous image-based data mining studies by revealing a strong association between dose to the base of the heart and overall survival. For the first time, an interaction between baseline cardiac health and heart base dose was identified, potentially suggesting preexisting cardiac dysfunction exacerbates the impact of heart dose on survival.

Impact of rigid and nonrigid registration on the determination of 18F-FDG PET-based tumour volume and standardized uptake value in patients with lung cancer.

PURPOSE: Assessment of the metabolically active tumour tissue by FDG PET is evolving for use in the diagnosis of non-small-cell lung cancer (NSCLC), in the planning of radiotherapy, and in follow-up and response evaluation. For exact evaluation accurate registration of PET and CT data is required. The registration process is usually based on rigid algorithms; however, nonrigid algorithms are increasingly being used. The influence of the registration method on FDG PET-based standardized uptake value (SUVmax) and metabolic tumour volume (MTV) definition has not yet been evaluated. We compared intra- and interindividual differences in SUV and MTV between rigid- and nonrigid-registered PET and CT acquired during different breathing manoeuvres. METHODS: The study group comprised 28 radiotherapy candidates with histologically proven NSCLC who underwent FDG PET acquisition and three CT acquisitions (expiration - EXP, inspiration - INS, mid-breath-hold - MID). All scans were registered with both a rigid (R) and a nonrigid (NR) procedure resulting in six fused datasets: R-INS, R-EXP, R-MID, NR-INS, NR-EXP and NR-MID. For the delineation of MTVs a contrast-oriented contouring algorithm developed in-house was used. To accelerate the delineation a semiautomatic software prototype was utilized. RESULTS: Tumour mean SUVmax did not differ for R and NR registration (R 17.5 ± 7, NR 17.4 ± 7; p=0.2). The mean MTV was higher by 3 ± 12 ml (p=0.02) in the NR group than in the R group, as was the mean tumour diameter (by 0.1 ± 0.2 cm; p<0.01). With respect to the three different breathing manoeuvres, there were no differences in MTV in the R group (p > 0.7). In intraindividual comparison there were no significant differences in MTVs concerning the registration pairs R-EXP (68 ± 88 ml) vs. NR-EXP (69 ± 85 ml) und R-MID (68 ± 86 ml) vs. NR-MID (69 ± 83 ml) (both p > 0.4). However, the MTVs were larger after NR registration during inspiration (R-INS 68 ± 82 vs. NR-INS 78 ± 93 ml; p=0.02). CONCLUSION: The use of nonrigid algorithms may lead to a change in MTV, whose extent is influenced by the breathing manoeuvre on CT. Nonrigid registration methods cannot be recommended for the definition of MTV if the CT scan is performed during inspiration. The choice of registration algorithm has no significant impact on SUVmax.

Impact of radiotherapy protocol adherence in NSCLC patients treated with concurrent chemoradiation: RTQA results of the PET-Plan trial.

INTRODUCTION: The success of intensification and personalisation of the curative treatment of non-small cell lung cancer (NSCLC) is strongly associated with the precision in radiotherapy. Here, we evaluate the impact of radiotherapy protocol adherence in a prospective multicentre trial. METHODS: In the open-label, randomised, controlled PET-Plan trial, patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume delineation informed by 1F-FDG PET and CT plus elective nodal irradiation (arm A) or target volumes informed by PET alone (arm B) and received iso-toxically dose-escalated concurrent chemoradiation. The prospectively organised quality assurance program (RTQA) included individual case review by predefined criteria. For evaluation, protocol adherence was scored as per protocol (pP), with minor (miD), intermediate (inD) and major (maD) deviations. In order to exclude biases through patients who discontinued treatment, patients who received ≥60 Gy were additionally analysed. RESULTS: Between 05/2009-11/2016, 205 patients were randomized, 204 patients started treatment according to protocol of which 31 (15%) patients had maD. Patients with maD had an inferior overall survival (OS) (HR 2.9, 95% CI 1.8-4.4, p < 0.0001) and a higher risk of loco-regional progression (HR 5.7, 95% CI 2.7-11.1, p < 0.0001). These results were significant also in the subgroup of patients receiving ≥ 60 Gy. Patients with maD concerning normal tissue delineation and/or dose constraints had a worse OS (p = 0.006) although no higher incidence of grade ≥ 3 toxicities. CONCLUSIONS: Non-adherence to the radiotherapy protocol was associated with an inferior OS and loco-regional control. These results underline the importance of RTQA.

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer-A Secondary Analysis of the PET Plan Trial.

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m2 (day 1, 22) and vinorelbin 15 mg/m2 (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m2 (day 1-5, 29-33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1-5, 29-33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician's discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 (p = 0.015, p = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, p = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias.

A contrast-oriented algorithm for FDG-PET-based delineation of tumour volumes for the radiotherapy of lung cancer: derivation from phantom measurements and validation in patient data.

PURPOSE: An easily applicable algorithm for the FDG-PET-based delineation of tumour volumes for the radiotherapy of lung cancer was developed by phantom measurements and validated in patient data. METHODS: PET scans were performed (ECAT-ART tomograph) on two cylindrical phantoms (phan1, phan2) containing glass spheres of different volumes (7.4-258 ml) which were filled with identical FDG concentrations. Gradually increasing the activity of the fillable background, signal-to-background ratios from 33:1 to 2.5:1 were realised. The mean standardised uptake value (SUV) of the region-of-interest (ROI) surrounded by a 70% isocontour (mSUV(70)) was used to represent the FDG accumulation of each sphere (or tumour). Image contrast was defined as C=(mSUV(70)-BG)/BG where BG is the mean background - SUV. For the spheres of phan1, the threshold SUVs (TS) best matching the known sphere volumes were determined. A regression function representing the relationship between TS/(mSUV(70) - BG) and C was calculated and used for delineation of the spheres in phan2 and the gross tumour volumes (GTVs) of eight primary lung tumours. These GTVs were compared to those defined using CT. RESULTS: The relationship between TS/(mSUV(70) - BG) and C is best described by an inverse regression function which can be converted to the linear relationship TS=a x mSUV(70)+b x BG. Using this algorithm, the volumes delineated in phan2 differed by only -0.4 to +0.7 mm in radius from the true ones, whilst the PET-GTVs differed by only -0.7 to +1.2 mm compared with the values determined by CT. CONCLUSION: By the contrast-oriented algorithm presented in this study, a PET-based delineation of GTVs for primary tumours of lung cancer patients is feasible.

Magnetic Resonance Lymphography at 9.4 T Using a Gadolinium-Based Nanoparticle in Rats: Investigations in Healthy Animals and in a Hindlimb Lymphedema Model.

OBJECTIVES: Magnetic resonance lymphography (MRL) in small animals is a promising but challenging tool in preclinical lymphatic research. In this study, we compared the gadolinium (Gd)-based nanoparticle AGuIX with Gd-DOTA for interstitial MRL in healthy rats and in a chronic rat hindlimb lymphedema model. MATERIALS AND METHODS: A comparative study with AGuIX and Gd-DOTA for interstitial MRL was performed in healthy Lewis rats (n = 6). For this purpose, 75 µL of 3 mM AGuIX (containing 30 mM Gd-DOTA side residues) and 75 µL 30 mM Gd-DOTA were injected simultaneously in the right and left hindlimbs. Repetitive high-resolution, 3-dimensional time-of-flight gradient recalled echo MRL sequences were acquired over a period of 90 minutes using a 9.4 T animal scanner. Gadofosveset-enhanced MR angiography and surgical dissection after methylene blue injection served as supportive imaging techniques. In a subsequent proof-of-principle study, AGuIX-based MRL was investigated in a hindlimb model of chronic lymphedema (n = 4). Lymphedema of the right hindlimbs was induced by means of popliteal and inguinal lymphadenectomy and irradiation with 20 Gy. The nonoperated left hindlimbs served as intraindividual controls. Six, 10, and 14 weeks after lymphadenectomy, MRL investigations were performed to objectify lymphatic reorganization. Finally, skin samples of the lymphedematous and the contralateral control hindlimbs were analyzed by means of histology and immunohistochemistry. RESULTS: AGuIX-based MRL resulted in high-resolution anatomical depiction of the rodent hindlimb lymphatic system. Signal-to-noise ratio and contrast-to-noise ratio of the popliteal lymph node were increased directly after injection and remained significantly elevated for up to 90 minutes after application. AGuIX provided significantly higher and prolonged signal intensity enhancement as compared with Gd-DOTA. Furthermore, AGuIX-based MRL demonstrated lymphatic regeneration in the histopathologically verified chronic lymphedema model. Collateral lymphatic vessels were detectable 6 weeks after lymphadenectomy. CONCLUSIONS: This study demonstrates that AGuIX is a suitable contrast agent for preclinical interstitial MRL in rodents. AGuIX yields anatomical imaging of lymphatic vessels with diameters greater than 200 µm. Moreover, it resides in the lymphatic system for a prolonged time. AGuIX may therefore facilitate high-resolution MRL-based analyses of the lymphatic system in rodents.

Practical integration of [18F]-FDG-PET and PET-CT in the planning of radiotherapy for non-small cell lung cancer (NSCLC): the technical basis, ICRU-target volumes, problems, perspectives.

The value of positron emission tomography using [18F]-fluoro-deoxy-glucose (FDG-PET) for pretherapeutic evaluation of patients with non-small cell lung cancer (NSCLC) is beyond doubt. Due to the increasing availability of PET and PET-CT scanners the method is now widely available, and its technical integration has become possible for radiotherapy planning systems. Due to the depiction of malignant tissue with high diagnostic accuracy, the use of FDG-PET in radiotherapy planning of NSCLC is very promising. However, by uncritical application, PET could impair rather than improve the prognosis of patients. Therefore, in the present paper we give an overview of technical factors influencing PET and PET-CT data, and their consequences for radiotherapy planning. We further review the relevant literature concerning the diagnostic value of FDG-PET and on the integration of FDG-PET data in RT planning for NSCLC. We point out the possible impact in gross tumor volume (GTV) definition and describe methods of target volume contouring of the primary tumor, as well as concepts for the integration of diagnostic information on lymph node involvement into the clinical target volume (CTV), and the possible implications of PET data on the definition of the planning target volume (PTV). Finally, we give an idea of the possible future use of tracers other than [18F]-FDG in lung cancer.

The Impact of Diffusion-Weighted MRI on the Definition of Gross Tumor Volume in Radiotherapy of Non-Small-Cell Lung Cancer.

OBJECTIVE: The study was designed to evaluate diffusion-weighted magnetic resonance imaging (DWI) vs. PET-CT of the thorax in the determination of gross tumor volume (GTV) in radiotherapy planning of non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Eligible patients with NSCLC who were supposed to receive definitive radio(chemo)therapy were prospectively recruited. For MRI, a respiratory gated T2-weighted sequence in axial orientation and non-gated DWI (b = 0, 800, 1,400 and apparent diffusion coefficient map [ADC]) were acquired on a 1.5 Tesla scanner. Primary tumors were delineated on FDG-PET/CT (stGTV) and DWI images (dwGTV). The definition of stGTV was based on the CT and visually adapted to the FDG-PET component if indicated (e.g., in atelectasis). For DWI, dwGTV was visually determined and adjusted for anatomical plausibility on T2w sequences. Beside a statistical comparison of stGTV and dwGTB, spatial agreement was determined with the "Hausdorff-Distance" (HD) and the "Dice Similarity Coefficient" (DSC). RESULTS: Fifteen patients (one patient with two synchronous NSCLC) were evaluated. For 16 primary tumors with UICC stages I (n = 4), II (n = 3), IIIA (n = 2) and IIIB (n = 7) mean values for dwGTV were significantly larger than those of stGTV (76.6 ± 84.5 ml vs. 66.6 ± 75.2 ml, p<0.01). The correlation of stGTV and dwGTV was highly significant (r = 0.995, p<0.001). Yet, some considerable volume deviations between these two methods were observed (median 27.5%, range 0.4-52.1%). An acceptable agreement between dwGTV and stGTV regarding the spatial extent of primary tumors was found (average HD: 2.25 ± 0.7 mm; DC 0.68 ± 0.09). CONCLUSION: The overall level of agreement between PET-CT and MRI based GTV definition is acceptable. Tumor volumes may differ considerably in single cases. DWI-derived GTVs are significantly, yet modestly, larger than their PET-CT based counterparts. Prospective studies to assess the safety and efficacy of DWI-based radiotherapy planning in NSCLC are warranted.

Comparison of different methods for delineation of 18F-FDG PET-positive tissue for target volume definition in radiotherapy of patients with non-Small cell lung cancer.

UNLABELLED: PET with (18)F-FDG ((18)F-FDG PET) is increasingly used in the definition of target volumes for radiotherapy, especially in patients with non-small cell lung cancer (NSCLC). In this context, the delineation of tumor contours is crucial and is currently done by different methods. This investigation compared the gross tumor volumes (GTVs) resulting from 4 methods used for this purpose in a set of clinical cases. METHODS: Data on the primary tumors of 25 patients with NSCLC were analyzed. They had (18)F-FDG PET during initial tumor staging. Thereafter, additional PET of the thorax in treatment position was done, followed by planning CT. CT and PET images were coregistered, and the data were then transferred to the treatment planning system (PS). Sets of 4 GTVs were generated for each case by 4 methods: visually (GTV(vis)), applying a threshold of 40% of the maximum standardized uptake value (SUV(max); GTV(40)), and using an isocontour of SUV = 2.5 around the tumor (GTV(2.5)). By phantom measurements we determined an algorithm, which rendered the best fit comparing PET with CT volumes using tumor and background intensities at the PS. Using this method as the fourth approach, GTV(bg) was defined. A subset of the tumors was clearly delimitable by CT. Here, a GTV(CT) was determined. RESULTS: We found substantial differences between the 4 methods of up to 41% of the GTV(vis). The differences correlated with SUV(max), tumor homogeneity, and lesion size. The volumes increased significantly from GTV(40) (mean 53.6 mL) < GTV(bg) (94.7 mL) < GTV(vis) (157.7 mL) and GTV(2.5) (164.6 mL). In inhomogeneous lesions, GTV(40) led to visually inadequate tumor coverage in 3 of 8 patients, whereas GTV(bg) led to intermediate, more satisfactory volumes. In contrast to all other GTVs, GTV(40) did not correlate with the GTV(CT). CONCLUSION: The different techniques of tumor contour definition by (18)F-FDG PET in radiotherapy planning lead to substantially different volumes, especially in patients with inhomogeneous tumors. Here, the GTV(40) does not appear to be suitable for target volume delineation. More complex methods, such as system-specific contrast-oriented algorithms for contour definition, should be further evaluated with special respect to patient data.

Dose distribution and tumor control probability in out-of-field lymph node stations in intensity modulated radiotherapy (IMRT) vs 3D-conformal radiotherapy (3D-CRT) of non-small-cell lung cancer: an in silico analysis.

BACKGROUND: The advent of IMRT and image-guided radiotherapy (IGRT) in combination with involved-field radiotherapy (IF-RT) in inoperable non-small-cell lung cancer results in a decreased incidental dose deposition in elective nodal stations. While incidental nodal irradiation is considered a relevant by-product of 3D-CRT to control microscopic disease this planning study analyzed the impact of IMRT on dosimetric parameters and tumor control probabilities (TCP) in elective nodal stations in direct comparison with 3D-CRT. METHODS AND MATERIALS: The retrospective planning study was performed on 41 patients with NSCLC (stages II-III). The CTV was defined as the primary tumor (GTV + 3 mm) and all FDG-PET-positive lymph node stations. As to the PTV (CTV + 7 mm), both an IMRT plan and a 3D-CRT plan were established. Plans were escalated until the pre-defined dose-constraints of normal tissues (spinal cord, lung, esophagus and heart) were reached. Additionally, IMRT plans were normalized to the total dose of the corresponding 3D-CRT. For two groups of out-of-field mediastinal node stations (all lymph node stations not included in the CTV (LNall_el) and those directly adjacent to the CTV (LNadj_el)) the equivalent uniform dose (EUD) and the TCP (for microscopic disease a D50 of 36.5 Gy was assumed) for the treatment with IMRT vs 3D-CRT were calculated. RESULTS: In comparison, a significantly higher total dose for the PTV could be achieved with the IMRT planning as opposed to conventional 3D-CRT planning (74.3 Gy vs 70.1 Gy; p = 0.03). In identical total reference doses, the EUD of LNadj_el is significantly lower with IMRT than with 3D-CRT (40.4 Gy vs. 44.2 Gy. P = 0.05) and a significant reduction of TCP with IMRT vs 3D-CRT was demonstrated for LNall_el and LNadj_el (12.6% vs. 14.8%; and 23.6% vs 27.3%, respectively). CONCLUSIONS: In comparison with 3D-CRT, IMRT comes along with a decreased EUD in out-of-field lymph node stations. This translates into a statistically significant decrease in TCP-values. Yet, the combination of IF-RT and IMRT leads to a significantly better sparing of normal tissues and higher total doses whereas the potential therapeutic drawback of decreased incidental irradiation of elective lymph nodes is moderate.

Visualisation of respiratory tumour motion and co-moving isodose lines in the context of respiratory gating, IMRT and flattening-filter-free beams.

Respiratory motion during percutaneous radiotherapy can be considered based on respiration-correlated computed tomography (4DCT). However, most treatment planning systems perform the dose calculation based on a single primary CT data set, even though cine mode displays may allow for a visualisation of the complete breathing cycle. This might create the mistaken impression that the dose distribution were independent of tumour motion. We present a movie visualisation technique with the aim to direct attention to the fact that the dose distribution migrates to some degree with the tumour and discuss consequences for gated treatment, IMRT plans and flattening-filter-free beams. This is a feasibility test for a visualisation of tumour and isodose motion. Ten respiratory phases are distinguished on the CT, and the dose distribution from a stationary IMRT plan is calculated on each phase, to be integrated into a movie of tumour and dose motion during breathing. For one example patient out of the sample of five lesions, the plan is compared with a gated treatment plan with respect to tumour coverage and lung sparing. The interplay-effect for small segments in the IMRT plan is estimated. While the high dose rate, together with the cone-shaped beam profile, makes the use of flattening-filter-free beams more problematic for conformal and IMRT treatment, it can be the option of choice if gated treatment is preferred. The different effects of respiratory motion, dose build-up and beam properties (segments and flatness) for gated vs. un-gated treatment can best be considered if planning is performed on the full 4DCT data set, which may be an incentive for future developments of treatment planning systems.

F-18-FDG-PET confined radiotherapy of locally advanced NSCLC with concomitant chemotherapy: results of the PET-PLAN pilot trial.

PURPOSE: The integration of fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the process of radiotherapy (RT) planning of locally advanced non-small-cell lung cancer (NSCLC) may improve diagnostic accuracy and minimize interobserver variability compared with target volume definition solely based on computed tomography. Furthermore, irradiating only FDG-PET-positive findings and omitting elective nodal regions may allow dose escalation by treating smaller volumes. The aim of this prospective pilot trial was to evaluate the therapeutic safety of FDG-PET-based RT treatment planning with an autocontour-derived delineation of the primary tumor. METHODS AND MATERIALS: Eligible patients had Stages II-III inoperable NSCLC, and simultaneous, platinum-based radiochemotherapy was indicated. FDG-PET and computed tomography acquisitions in RT treatment planning position were coregistered. The clinical target volume (CTV) included the FDG-PET-defined primary tumor, which was autodelineated with a source-to-background algorithm, plus FDG-PET-positive lymph node stations. Limited by dose restrictions for normal tissues, prescribed total doses were in the range of 66.6 to 73.8 Gy. The primary endpoint was the rate of out-of-field isolated nodal recurrences (INR). RESULTS: As per intent to treat, 32 patients received radiochemotherapy. In 15 of these patients, dose escalation above 66.6 Gy was achieved. No Grade 4 toxicities occurred. After a median follow-up time of 27.2 months, the estimated median survival time was 19.3 months. During the observation period, one INR was observed in 23 evaluable patients. CONCLUSIONS: FDG-PET-confined target volume definition in radiochemotherapy of NSCLC, based on a contrast-oriented source-to-background algorithm, was associated with a low risk of INR. It might provide improved tumor control because of dose escalation.

FDG-PET-based radiotherapy planning in lung cancer: optimum breathing protocol and patient positioning--an intraindividual comparison.

PURPOSE: Fluoro-2-deoxy-d-glucose (FDG)-positron emission tomography (PET) and PET/computed tomography (CT) are increasingly used for radiotherapy (RT) planning in patients with non-small-cell lung carcinoma. The planning process often is based on separately acquired FDG-PET/CT and planning CT scans. We compared intraindividual differences between PET acquired in diagnostic (D-PET) and RT treatment position (RT-PET) coregistered with planning CTs acquired using different breathing protocols. METHODS AND MATERIALS: Sixteen patients with non-small-cell lung carcinoma underwent two PET acquisitions (D-PET and RT-PET) and three planning CT acquisitions (expiration [EXP], inspiration [INS], and mid-breath hold [MID]) on the same day. All scans were rigidly coregistered, resulting in six fused data sets: D-INS, D-EXP, D-MID, RT-INS, RT-EXP, and RT-MID. Fusion accuracy was assessed by three readers at eight anatomic landmarks, lung apices, aortic arch, heart, spine, sternum, carina, diaphragm, and tumor, by using an alignment score ranging from 1 (no alignment) to 5 (exact alignment). RESULTS: The RT-PET showed better alignment with any CT than D-PET (p < 0.001). With regard to breathing, RT-MID showed the best mean alignment score (3.7 +/- 1.0), followed by RT-EXP (3.5 +/- 0.9) and RT-INS (3.0 +/- 0.8), with all differences significant (p < 0.001). Comparing alignment scores with regard to anatomic landmarks, the largest deviations were found at the diaphragm, heart, and apices. Overall, there was fair agreement (kappa = 0.48; p < 0.001) among the three readers. CONCLUSIONS: Significantly better fusion of PET and planning CT can be reached with PET acquired in the RT position. The best intraindividual fusion results are obtained with the planning CT performed during mid-breath hold. Our data justify the acquisition of a separate planning PET in RT treatment position if only a diagnostic PET scan is available.

Nonrigid versus rigid registration of thoracic 18F-FDG PET and CT in patients with lung cancer: an intraindividual comparison of different breathing maneuvers.

UNLABELLED: In lung cancer, (18)F-FDG PET, CT, and (18)F-FDG PET/CT are used for noninvasive staging and therapy planning. Even with improved image registration techniques-especially in the modern hybrid PET/CT scanners-inaccuracies in the fusion process may occur, leading to errors in image interpretation. The aim of this study was to investigate by an intraindividual analysis whether, in comparison with a rigid algorithm, a nonrigid registration algorithm improves the quality of fusion between (18)F-FDG PET and CT. METHODS: Sixteen patients with histologically proven non-small cell lung cancer underwent a thoracic (18)F-FDG PET acquisition in radiotherapy treatment position and 3 CT acquisitions (expiration, inspiration, and mid breath-hold) on the same day. All scans were registered with rigid and nonrigid procedures, resulting in 6 fused datasets: rigid inspiration, rigid expiration, rigid mid breath-hold, nonrigid inspiration, nonrigid expiration, and nonrigid mid breath-hold. The quality of alignment was assessed by 3 experienced readers at 8 anatomic landmarks: lung apices, aortic arch, heart, spine, sternum, carina, diaphragm, and tumor using an alignment score ranging from 1 (no alignment) to 5 (exact alignment). RESULTS: Nonrigid PET/CT showed better alignment than rigid PET/CT (3.5 +/- 0.7 vs. 3.3 +/- 0.7, P < 0.001). Regarding the breathing maneuver, no difference between nonrigid mid breath-hold and rigid mid breath-hold was observed. In contrast, the alignment quality significantly improved from rigid expiration to nonrigid expiration (3.4 +/- 0.7 vs. 3.6 +/- 0.7, P < 0.001) and from rigid inspiration to nonrigid inspiration (3.1 +/- 0.7 vs. 3.3 +/- 0.7, P < 0.001). With regard to individual landmarks, an improvement in fusion quality through the use of nonrigid registration was obvious at the lung apices, carina, and aortic arch. CONCLUSION: The alignment quality of thoracic (18)F-FDG PET/CT exhibits a marked dependence on the breathing maneuver performed during the CT acquisition, as demonstrated in an intraindividual comparison. Nonrigid registration is a significant improvement over rigid registration if the CT is performed during full inspiration or full expiration. The best fusion results are obtained with the CT performed at mid breath-hold using rigid registration, without an improvement using nonrigid algorithms.

Target volume definition for 18F-FDG PET-positive lymph nodes in radiotherapy of patients with non-small cell lung cancer.

PURPOSE: FDG PET is increasingly used in radiotherapy planning. Recently, we demonstrated substantial differences in target volumes when applying different methods of FDG-based contouring in primary lung tumours (Nestle et al., J Nucl Med 2005;46:1342-8). This paper focusses on FDG-positive mediastinal lymph nodes (LN(PET)). METHODS: In our institution, 51 NSCLC patients who were candidates for radiotherapy prospectively underwent staging FDG PET followed by a thoracic PET scan in the treatment position and a planning CT. Eleven of them had 32 distinguishable non-confluent mediastinal or hilar nodal FDG accumulations (LN(PET)). For these, sets of gross tumour volumes (GTVs) were generated at both acquisition times by four different PET-based contouring methods (visual: GTV(vis); 40% SUVmax: GTV40; SUV=2.5: GTV2.5; target/background (T/B) algorithm: GTV(bg)). RESULTS: All differences concerning GTV sizes were within the range of the resolution of the PET system. The detectability and technical delineability of the GTVs were significantly better in the late scans (e.g. p = 0.02 for diagnostic application of SUVmax = 2.5; p = 0.0001 for technical delineability by GTV2.5; p = 0.003 by GTV40), favouring the GTV(bg) method owing to satisfactory overall applicability and independence of GTVs from acquisition time. Compared with CT, the majority of PET-based GTVs were larger, probably owing to resolution effects, with a possible influence of lesion movements. CONCLUSION: For nodal GTVs, different methods of contouring did not lead to clinically relevant differences in volumes. However, there were significant differences in technical delineability, especially after early acquisition. Overall, our data favour a late acquisition of FDG PET scans for radiotherapy planning, and the use of a T/B algorithm for GTV contouring.