Michel Öllers

The PET-boost randomised phase II dose-escalation trial in non-small cell lung cancer

PURPOSE The local site of relapse in non-small cell lung cancer (NSCLC) is primarily located in the high FDG uptake region of the primary tumour prior to treatment. A phase II PET-boost trial (NCT01024829) randomises patients between dose-escalation of the entire primary tumour (arm A) or to the high FDG uptake region inside the primary tumour (>50% SUV(max)) (arm B), whilst giving 66 Gy in 24 fractions to involved lymph nodes. We analysed the planning results of the first 20 patients for which both arms A and B were planned. METHODS Boost dose levels were escalated up to predefined normal tissue constraints with an equal mean lung dose in both arms. This also forces an equal mean PTV dose in both arms, hence testing pure dose-redistribution. Actual delivered treatment plans from the ongoing clinical trial were analysed. Patients were randomised between arms A and B if dose-escalation to the primary tumour in arm A of at least 72 Gy in 24 fractions could be safely planned. RESULTS 15/20 patients could be escalated to at least 72 Gy. Average prescribed fraction dose was 3.27±0.31 Gy [3.01-4.28 Gy] and 3.63±0.54 Gy [3.20-5.40 Gy] for arms A and B, respectively. Average mean total dose inside the PTV of the primary tumour was comparable: 77.3±7.9 Gy vs. 77.5±10.1 Gy. For the boost region dose levels of on average 86.9±14.9 Gy were reached. No significant dose differences between both arms were observed for the organs at risk. Most frequent observed dose-limiting constraints were the mediastinal structures (13/15 and 14/15 for arms A and B, respectively), and the brachial plexus (3/15 for both arms). CONCLUSION Dose-escalation using an integrated boost could be achieved to the primary tumour or high FDG uptake regions whilst keeping the pre-defined dose constraints.

Mature Results of an Individualized Radiation Dose Prescription Study Based on Normal Tissue Constraints in Stages I to III Non-Small-Cell Lung Cancer

PURPOSE We previously showed that individualized radiation dose escalation based on normal tissue constraints would allow safe administration of high radiation doses with low complication rate. Here, we report the mature results of a prospective, single-arm study that used this individualized tolerable dose approach. PATIENTS AND METHODS In total, 166 patients with stage III or medically inoperable stage I to II non-small-cell lung cancer, WHO performance status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of lungs for carbon monoxide >or= 30% were included. Patients were irradiated using an individualized prescribed total tumor dose (TTD) based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential chemoradiation was administered. The primary end point was overall survival (OS), and the secondary end point was toxicity according to Common Terminology Criteria of Adverse Events (CTCAE) v3.0. RESULTS The median prescribed TTD was 64.8 Gy (standard deviation, +/- 11.4 Gy) delivered in 25 +/- 5.8 days. With a median follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7% and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%; grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable. CONCLUSION Individualized prescribed radical radiotherapy based on normal tissue constraints with sequential chemoradiation shows survival rates that come close to results of concurrent chemoradiation schedules, with acceptable acute and late toxicity. A prospective randomized study is warranted to further investigate its efficacy.

Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging

Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [18F]HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [18F]HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P < 0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 ± 0.926 and optimal imaging properties 4 h after injection. [18F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [18F]HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [18F]HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P < 0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P < 0.001) in [18F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P < 0.05). [18F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.

Optimal gating compared to 3D and 4D PET reconstruction for characterization of lung tumours

PurposeWe investigated the added value of a new respiratory amplitude-based PET reconstruction method called optimal gating (OG) with the aim of providing accurate image quantification in lung cancer.MethodsFDG-PET imaging was performed in 26 lung cancer patients during free breathing using a 24-min list-mode acquisition on a PET/CT scanner. The data were reconstructed using three methods: standard 3D PET, respiratory-correlated 4D PET using a phase-binning algorithm, and OG. These datasets were compared in terms of the maximum SUV (SUVmax) in the primary tumour (main endpoint), noise characteristics, and volumes using thresholded regions of SUV 2.5 and 40% of the SUVmax.ResultsSUVmax values from the 4D method (13.7 ± 5.6) and the OG method (14.1 ± 6.5) were higher (4.9 ± 4.8%, p < 0.001 and 6.9 ± 8.8%, p < 0.001, respectively) than that from the 3D method (13.1 ± 5.4). SUVmax did not differ between the 4D and OG methods (2.0 ± 8.4%, p = NS). Absolute and relative threshold volumes did not differ between methods, except for the 40% SUVmax volume in which the value from the 3D method was lower than that from the 4D method (−5.3 ± 7.1%, p = 0.007). The OG method exhibited less noise than the 4D method. Variations in volumes and SUVmax of up to 40% and 27%, respectively, of the individual gates of the 4D method were also observed.ConclusionThe maximum SUVs from the OG and 4D methods were comparable and significantly higher than that from the 3D method, yet the OG method was visibly less noisy than the 4D method. Based on the better quantification of the maximum and the less noisy appearance, we conclude that OG PET is a better alternative to both 3D PET, which suffers from breathing averaging, and the noisy images of a 4D PET.

Response Assessment Using 18F-FDG PET Early in the Course of Radiotherapy Correlates with Survival in Advanced-Stage Non–Small Cell Lung Cancer

This study investigated the possibility of early response assessment based on 18F-FDG uptake during radiotherapy with respect to overall survival in patients with non–small cell lung cancer. Methods: 18F-FDG PET/CT was performed before radiotherapy and was repeated in the second week of radiotherapy for 34 consecutive lung cancer patients. The CT volume and standardized uptake value (SUV) parameters of the primary tumor were quantified at both time points. Changes in volume and SUV parameters correlated with 2-y overall survival. Results: The average change in mean SUV in the primary tumor of patients with a 2-y survival was a decrease by 20% ± 21%—significantly different (P < 0.007) from nonsurvivors, who had an increase by 2% ± 22%. A sensitivity and specificity of 63% and 93%, respectively, to separate the 2 groups was reached for a decrease in mean SUV of 15%. Survival curves were significantly different using this cutoff (P = 0.001). The hazard ratio for a 1% decrease in mean SUV was 1.032 (95% confidence interval, 1.010–1.055). Changes in tumor volume defined on CT did not correlate with overall survival. Conclusion: The use of repeated 18F-FDG PET to assess treatment response early during radiotherapy is possible in patients undergoing radiotherapy or sequential or concurrent chemoradiotherapy. A decrease in 18F-FDG uptake by the primary tumor correlates with higher long-term overall survival.

Is high-dose stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) overkill? A systematic review

BACKGROUND AND PURPOSE For stereotactic body radiotherapy (SBRT), typically a scheme of 60 Gy in 3-8 fractions is applied, producing local tumour control rates around 90%. The dose specification is in one point only and ignores possible underdosages at the edge of the planning target volume (PTV). We investigated the doses at the edge of the PTV and correlated this with local tumour control with the aim to shed light on the radiation dose needed to eradicate stage I NSCLC. MATERIALS AND METHODS Published data on the freedom from local progression (FFLP) data from SBRT and accelerated high-dose conventional radiotherapy series for stage I NSCLC with a follow up of at least 30 months were included. The EQD(2,T) was calculated from the dose at the periphery of the PTV. RESULTS Fifteen studies for SBRT (1076 patients) showed a median FFLP of 88.0±10.4% with a median EQD(2,T) of 76.9±17.4 Gy. The median FFLP was 87.6±6.0% for the accelerated schedules with an EQD(2,T) of 86.9±39.1 Gy, respectively. No significant relation was found between FFLP and the EQD(2,T) (p=0.23). CONCLUSIONS Several fractionated and accelerated schedules with equal biological doses achieve the same tumour control rates as SBRT. Lower, but more uniform doses to the whole PTV may be sufficient to achieve similar control rates, with the possibility to deliver SBRT in adapted schedules, beneficial to centrally located tumours in the vicinity of critical structures like the oesophagus and great vessels.

Accurate Prediction of Pathological Rectal Tumor Response after Two Weeks of Preoperative Radiochemotherapy Using 18F-Fluorodeoxyglucose-Positron Emission Tomography-Computed Tomography Imaging

PURPOSE To determine the optimal time point for repeated (18)F-fluorodeoxyglucose-positron emission tomography (PET)-CT imaging during preoperative radiochemotherapy (RCT) and the best predictive factor for the prediction of pathological treatment response in patients with locally advanced rectal cancer. METHODS AND MATERIALS A total of 30 patients referred for preoperative RCT treatment were included in this prospective study. All patients underwent sequential PET-CT imaging at four time points: prior to therapy, at day 8 and 15 during RCT, and shortly before surgery. Tumor metabolic treatment responses were correlated with the pathological responses by evaluation of the tumor regression grade (TRG) and the pathological TN (ypT) stage of the resected specimen. RESULTS Based on their TRG evaluations, 13 patients were classified as pathological responders, whereas 17 patients were classified as pathological nonresponders. The response index (RI) for the maximum standardized uptake value (SUV(max)) on day 15 of RCT was found to be the best predictive factor for the pathological response (area under the curve [AUC] = 0.87) compared to the RI on day 8 (AUC = 0.78) or the RI of presurgical PET imaging (AUC = 0.66). A cutoff value of 43% for the reduction of SUV(max) resulted in a sensitivity of 77% and a specificity of 93%. CONCLUSIONS The SUV(max)-based RI calculated after the first 2 weeks of RCT provided the best predictor of pathological treatment response, reaching AUCs of 0.87 and 0.84 for the TRG and the ypT stage, respectively. However, a few patients presented with peritumoral inflammatory reactions, which led to mispredictions. Exclusion of these patients further enhanced the predictive accuracy of PET imaging to AUCs of 0.97 and 0.89 for TRG and ypT, respectively.

Phased attenuation correction in respiration correlated computed tomography/positron emitted tomography

The motion of lung tumors with respiration causes difficulties in the imaging with computed tomography (CT) and positronemitted tomography (PET). Since an accurate knowledge of the position of the tumor and the surrounding tissues is needed for radiation treatment planning, it is important to improve CT/PET image acquisition. The purpose of this study was to evaluate the potential to improve image acquisition using phased attenuation correction in respiration correlated CT/PET, where data of both modalities were binned retrospectively. Respiration correlated scans were made on a Siemens Biograph Sensation 16 CT/PET scanner which was modified to make a low pitch CT scan and list mode PET scan possible. A lollipop phantom was used in the experiments. The sphere with a diameter of 3.1 cm was filled with approximately 20 MBq 18F-FDG. Three longitudinal movement amplitudes were tested: 2.5, 3.9, and 4.8 cm. After collection of the raw CT data, list mode PET data, and the respiratory signal CT/PET images were binned to ten phases with the help of in-house-built software. Each PET phase was corrected for attenuation with CT data of the corresponding phase. For comparison, the attenuation correction was also performed with nonrespiration correlated (non-RC) CT data. The volume and the amplitude of the movement were calculated for every phaseof both the CT and PET data (with phased attenuation correction). Maximum and average activity concentrations were compared between the phased and nonphased attenuation corrected PET. With a standard non-RC CT/PET scan, the volume was underestimated by as much as 46% in CT and the PET volume was overestimated to 370%. The volumes found with RC-CT/PET scanning had average deviations of 1.9% (+/- 4.8%) and 1.5% (+/- 3.4%) from the actual volume, for the CT and PET volumes, respectively. Evaluation of the maximum activity concentration showed a clear displacement in the images with non-RC attenuation correction, and activity values were on average14% (+/- 12%) lower than with phased attenuation correction. The standard deviation of the maximum activity values found in the different phases was a factor of 10 smaller when phased attenuation correction was applied. In this phantom study, we have shown that a combination of respiration correlated CT/PET scanning with application of phased attenuation correction can improve the imaging of moving objects and can lead to improved volume estimation and a more precise localization and quantification of the activity.

The Use of FDG-PET to Target Tumors by Radiotherapy

Fluorodeoxyglucose positron emission tomography (FDG-PET) plays an increasingly important role in radiotherapy, beyond staging and selection of patients. Especially for non-small cell lung cancer, FDG-PET has, in the majority of the patients, led to the safe decrease of radiotherapy volumes, enabling radiation dose escalation and, experimentally, redistribution of radiation doses within the tumor. In limited-disease small cell lung cancer, the role of FDG-PET is emerging. For primary brain tumors, PET based on amino acid tracers is currently the best choice, including high-grade glioma. This is especially true for low-grade gliomas, where most data are available for the use of 11C-MET (methionine) in radiation treatment planning. For esophageal cancer, the main advantage of FDG-PET is the detection of otherwise unrecognized lymph node metastases. In Hodgkin’s disease, FDG-PET is essential for involved-node irradiation and leads to decreased irradiation volumes while also decreasing geographic miss. FDG-PET’s major role in the treatment of cervical cancer with radiation lies in the detection of para-aortic nodes that can be encompassed in radiation fields. Besides for staging purposes, FDG-PET is not recommended for routine radiotherapy delineation purposes. It should be emphasized that using PET is only safe when adhering to strictly standardized protocols.ZusammenfassungDie Fluordesoxyglucose-Positronenemissionstomographie (FDG-PET) spielt eine zunehmende Bedeutung in der Strahlentherapie, neben der bereits etablierten Bedeutung für Tumorstaging und Patientenselektion. Insbesondere bei nichtkleinzelligen Lungenkarzinomen führt der Einsatz der FDG-PET in der Mehrzahl der Fälle zu einer unbedenklichen Abnahme des Strahlenvolumens, wodurch Dosiseskalationen und auf experimenteller Ebene selbst Dosisumverteilungen der Strahlendosis im Zielvolumen möglich werden. Bei kleinzelligen Lungenkarzinomen nimmt die Bedeutung der FDG-PET ebenfalls zu. Bei primären Hirntumoren stellt die Aminosäure-PET derzeit die beste Wahl dar, auch bei den hochgradigen Gliomen. Für die niedriggradigen Gliome favorisieren die meisten Daten den Einsatz von 11C-MET (Methionin) in der Strahlentherapieplanung. Beim Ösophaguskarzinom liegt der wesentliche Vorteil der FDG-PET in der Detektion von unerkannten Lymphknotenmetastasen. Beim Morbus Hodgkin ist die FDG-PET essentiell für die „involved-field“-Bestrahlung und führt zu einem reduzierten Strahlenvolumen bei gleichzeitig vermindertem Risko der geographischen Fehlbehandlung. Die bedeutendste Rolle der FDG-PET bei der Behandlung des Zervixkarzinoms liegt in der Detektion von paraaortalen Lymphknoten, die in das Bestrahlungsgebiet mit aufgenommen werden. Zusammenfassend wird die FDG-PET neben dem Einsatz beim primären Tumorstaging derzeit nicht für den Routineeinsatz bei der Einzeichnung des Zielvolumens in der Strahlentherapie empfohlen. Der Einsatz der FDG-PET sollte nur nach streng standardisierten Protokollen erfolgen.

Hypoxia imaging with [18F]HX4 PET in NSCLC patients: Defining optimal imaging parameters

BACKGROUND AND PURPOSE [(18)F]HX4 is a promising hypoxia PET-tracer. Uptake, spatio-temporal stability and optimal acquisition parameters for [(18)F]HX4 PET imaging were evaluated in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS [(18)F]HX4 PET/CT images of 15 NSCLC patients were acquired 2h and 4h after injection (p.i.). Maximum standardized-uptake-value (SUV(max)), tumor-to-blood-ratio (TBR(max)), hypoxic fraction (HF) and contrast-to-noise-ratio (CNR) were determined for all lesions. To evaluate spatio-temporal stability, DICE-similarity and Pearson correlation coefficients were calculated. Optimal acquisition-duration was assessed by comparing 30, 20, 10 and 5 min acquisitions. RESULTS Considerable uptake (TBR >1.4) was observed in 18/25 target lesions. TBR(max) increased significantly from 2 h (1.6 ± 0.3) to 4 h p.i. (2.0 ± 0.6). Uptake patterns at 2 h and 4 h p.i. showed a strong correlation (R=0.77 ± 0.10) with a DICE similarity coefficient of 0.69 ± 0.08 for the 30% highest uptake volume. Reducing acquisition-time resulted in significant changes in SUV(max) and CNR. TBR(max) and HF were only affected for scan-times of 5 min. CONCLUSIONS The majority of NSCLC lesions showed considerable [(18)F]HX4 uptake. The heterogeneous uptake pattern was stable between 2 h and 4 h p.i. [(18)F]HX4 PET imaging at 4 h p.i. is superior to 2 h p.i. to reach highest contrast. Acquisition time may be reduced to 10 min without significant effects on TBR(max) and HF.