P. Andrzejewski

Multiparametric [18F]Fluorodeoxyglucose/ [18F]Fluoromisonidazole Positron Emission Tomography/ Magnetic Resonance Imaging of Locally Advanced Cervical Cancer for the Non-Invasive Detection of Tumor Heterogeneity: A Pilot Study

Objectives To investigate fused multiparametric positron emission tomography/magnetic resonance imaging (MP PET/MRI) at 3T in patients with locally advanced cervical cancer, using high-resolution T2-weighted, contrast-enhanced MRI (CE-MRI), diffusion-weighted imaging (DWI), and the radiotracers [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoromisonidazol ([18F]FMISO) for the non-invasive detection of tumor heterogeneity for an improved planning of chemo-radiation therapy (CRT). Materials and Methods Sixteen patients with locally advanced cervix were enrolled in this IRB approved and were examined with fused MP [18F]FDG/ [18F]FMISO PET/MRI and in eleven patients complete data sets were acquired. MP PET/MRI was assessed for tumor volume, enhancement (EH)-kinetics, diffusivity, and [18F]FDG/ [18F]FMISO-avidity. Descriptive statistics and voxel-by-voxel analysis of MRI and PET parameters were performed. Correlations were assessed using multiple correlation analysis. Results All tumors displayed imaging parameters concordant with cervix cancer, i.e. type II/III EH-kinetics, restricted diffusivity (median ADC 0.80x10-3mm2/sec), [18F]FDG- (median SUVmax16.2) and [18F]FMISO-avidity (median SUVmax3.1). In all patients, [18F]FMISO PET identified the hypoxic tumor subvolume, which was independent of tumor volume. A voxel-by-voxel analysis revealed only weak correlations between the MRI and PET parameters (0.05–0.22), indicating that each individual parameter yields independent information and the presence of tumor heterogeneity. Conclusion MP [18F]FDG/ [18F]FMISO PET/MRI in patients with cervical cancer facilitates the acquisition of independent predictive and prognostic imaging parameters. MP [18F]FDG/ [18F]FMISO PET/MRI enables insights into tumor biology on multiple levels and provides information on tumor heterogeneity, which has the potential to improve the planning of CRT.

ART for head and neck patients: On the difference between VMAT and IMPT.

Abstract Anatomical changes in the head-and-neck (H&N) region during the course of treatment can cause deteriorated dose distributions. Different replanning strategies were investigated for volumetric modulated arc therapy (VMAT) and intensity-modulated proton therapy (IMPT). Material and methods. For six H&N patients two repeated computed tomography (CT) and magnetic resonance (MR) (CT1/MR1 at week 2 and CT2/MR2 at week 4) scans were acquired additionally to the initial planning CT/MR. Organs-at-risk (OARs) and three targets (CTV70Gy, CTV63Gy, CTV56Gy) were delineated on MRs and transferred to respective CT data set. Simultaneously integrated boost plans were created using VMAT (two arcs) and IMPT (four beams). To assess the need of replanning the initial VMAT and IMPT plans were recalculated on repeated CTs. Furthermore, VMAT and IMPT plans were replanned on the repeated CTs. A Demon algorithm was used for deformable registration of the repeated CTs with the initial CT and utilized for dose accumulation. Total dose estimations were performed to compare ART versus standard treatment strategies. Results. Dosimetric evaluation of recalculated plans on CT1 and CT2 showed increasing OAR doses for both, VMAT and IMPT. The target coverage of recalculated VMAT plans was considered acceptable in three cases, while for all IMPT plans it dropped. Adaptation of the treatment reduced D2% for brainstem by 6.7 Gy for VMAT and by 8 Gy for IMPT, for particular patients. These D2% reductions were reaching 9 Gy and 14 Gy for the spinal cord. ART improved target dose homogeneity, especially for protons, i.e. D2% decreased by up to 8 Gy while D98% increased by 1.2 Gy. Conclusion. ART showed benefits for both modalities. However, as IMPT is more conformal, the magnitude of dosimetric changes was more pronounced compared to VMAT. Large anatomic variations had a severe impact on treatment plan quality for both VMAT and IMPT. ART is justified in those cases irrespective of treatment modalities.

Feasibility of dominant intraprostatic lesion boosting using advanced photon-, proton- or brachytherapy

BACKGROUND AND PURPOSE Advancements in imaging and dose delivery enable boosting of the dominant intraprostatic lesions (DIL), while maintaining organs-at-risk (OAR) tolerances. This study aimed to assess the feasibility of DIL boosting for volumetric modulated arc therapy (VMAT), intensity modulated proton therapy (IMPT) and high dose rate brachytherapy (HDR-BT). MATERIAL AND METHODS DILs were defined on multiparametric magnetic resonance imaging and fused with planning CT for twelve patients. VMAT, IMPT and HDR-BT plans were created for each patient with an EQD2(α/β) DIL aimed at 111.6 Gy, PTV(initial) D(pres) was 80.9 Gy (EBRT) with CTV D90%=81.9 Gy (HDR-BT). Hard dose constraints were applied for OARs. RESULTS Higher boost doses were achieved with IMPT compared to VMAT, keeping major OAR doses at similar levels. Patient averaged EQD2(α/β) D50% to DIL were 110.7, 114.2 and 150.1 Gy(IsoE) for VMAT, IMPT and HDR-BT, respectively. Respective rectal wall D(mean) were 30.5±5.0, 16.7±3.6, 9.5±2.5 Gy(IsoE) and bladder wall D(mean) were 21.0±5.5, 15.6±4.3 and 6.3±2.2 Gy(IsoE). CONCLUSIONS DIL boosting was found to be feasible with all investigated techniques. Although OAR doses were higher than for standard treatment approach, the risk levels were reasonably low. HDR-BT was superior to VMAT and IMPT, both in terms of OAR sparing and DIL boosting.

Impact of hybrid PET/MR technology on multiparametric imaging and treatment response assessment of cervix cancer

BACKGROUND AND PURPOSE Multimodal tissue characterization by combined MRI and PET has high clinical potential in the context of sub-target definition for dose painting and response assessment but its clinical exploration is yet limited. The aim of this study was to prove the potential and feasibility of hybrid PET/MRI to non-invasively measure tumor hypoxia, perfusion and microstructure at one stop in tumors of the uterine cervix during chemoradiotherapy. MATERIAL AND METHODS Ten cervix cancer patients were subjected to simultaneous multiparametric PET/MRI with [18F]fluoromisonidazole ([18F]FMISO). Imaging was scheduled before, twice during and after chemoradiotherapy. Intra- and inter-time point analyses of the extracted parameters (i.e. ADC, Ktrans, ABrix, [18F]FMISO-tumor to background ratio (TBR)) were performed. The [18F]FMISO uptake- and ADC-spatio-temporal changes were assessed. RESULTS Patient averaged ADC values increased from baseline to follow up (1.03 ± 0.11/1.30 ± 0.13 × 10-3 mm2/s), while the TBR decreased (1.73 ± 0.24/1.36 ± 0.19), Ktrans dropped over time (0.17 ± 0.05/0.05 ± 0.05 min-1); for all above p < 0.05. None of these parameters correlated significantly on a voxel-by-voxel basis. Low-ADC regions spatially varied over time. There was pronounced reduction of the [18F]FMISO-avid volumes during treatment. CONCLUSIONS The suggested hybrid PET/MRI protocol to non-invasively investigate tumor hypoxia, perfusion and microstructure at one stop was feasible, revealing spatio-temporal response patterns that could be utilized for comprehensive sub-target definition for dose painting and response assessment.

Multiparametric [11C]Acetate positron emission tomography-magnetic resonance imaging in the assessment and staging of prostate cancer

Background The aim of this study was to evaluate whether MP [11C]Acetate PET-MRI enables an accurate differentiation of benign and malignant prostate tumors as well as local and distant staging. Materials and methods Fifty-six consecutive patients fulfilling the following criteria were included in this IRB-approved prospective study: elevated PSA levels or suspicious findings at digital rectal examination or TRUS; and histopathological verification. All patients underwent MP [11C]Acetate PET-MRI of the prostate performed on separate scanners with PET/CT using [11C]Acetate and 3T MP MR imaging. Appropriate statistical tests were used to determine diagnostic accuracy, local and distant staging. Results MP imaging with two MRI parameters (T2w and DWI) achieved the highest sensitivity, specificity, and diagnostic accuracy of 95%, 68.8%, and 88%, with an AUC of 0.82 for primary PCa detection. Neither assessments with a single parameter (AUC, 0.54–0.79), nor different combinations with up to five parameters (AUC, 0.67–0.79) achieved equally good results. MP [11C]Acetate PET-MRI improved local staging with a sensitivity, specificity, and diagnostic accuracy of 100%, 96%, and 97% compared to MRI alone with 72.2%, 100%, and 95.5%. MP [11C]Acetate PET-MRI correctly detected osseous and liver metastases in five patients. Conclusions MP [11C]Acetate PET-MRI merges morphologic with functional information, and allows insights into tumor biology. MP [11C]Acetate PET-MRI with two MRI-derived parameters (T2 and DWI) yields the highest diagnostic accuracy. The addition of more parameters does not improve diagnostic accuracy of primary PCa detection. MP [11C]Acetate PET-MRI facilitates improved local and distant staging, providing “one-stop” staging in patients with primary PCa, and therefore has the potential to improve therapy. Patient summary In this report we investigated MP [11C]Acetate PET-MRI for detection, local and distant staging of prostate cancer. We demonstrate that MP [11C]Acetate PET-MRI with two MRI-derived parameters (T2 and DWI) achieves the best diagnostic accuracy for primary prostate cancer detection and that MP [11C]Acetate PET-MRI enables an improved local and distant staging.

Association between pathology and texture features of multi parametric MRI of the prostate

The role of multi-parametric (mp)MRI in the diagnosis and treatment of prostate cancer has increased considerably. An alternative to visual inspection of mpMRI is the evaluation using histogram-based (first order statistics) parameters and textural features (second order statistics). The aims of the present work were to investigate the relationship between benign and malignant sub-volumes of the prostate and textures obtained from mpMR images. The performance of tumor prediction was investigated based on the combination of histogram-based and textural parameters. Subsequently, the relative importance of mpMR images was assessed and the benefit of additional imaging analyzed. Finally, sub-structures based on the PI-RADS classification were investigated as potential regions to automatically detect maligned lesions. Twenty-five patients who received mpMRI prior to radical prostatectomy were included in the study. The imaging protocol included T2, DWI, and DCE. Delineation of tumor regions was performed based on pathological information. First and second order statistics were derived from each structure and for all image modalities. The resulting data were processed with multivariate analysis, using PCA (principal component analysis) and OPLS-DA (orthogonal partial least squares discriminant analysis) for separation of malignant and healthy tissue. PCA showed a clear difference between tumor and healthy regions in the peripheral zone for all investigated images. The predictive ability of the OPLS-DA models increased for all image modalities when first and second order statistics were combined. The predictive value reached a plateau after adding ADC and T2, and did not increase further with the addition of other image information. The present study indicates a distinct difference in the signatures between malign and benign prostate tissue. This is an absolute prerequisite for automatic tumor segmentation, but only the first step in that direction. For the specific identified signature, DCE did not add complementary information to T2 and ADC maps.

Advanced Radiation DOSimetry phantom (ARDOS): a versatile breathing phantom for 4D radiation therapy and medical imaging

A novel breathing phantom was designed for being used in conventional and ion-beam radiotherapy as well as for medical imaging. Accurate dose delivery and patient safety are aimed to be verified for four-dimensional (4D) treatment techniques compensating for breathing-induced tumor motion. The phantom includes anthropomorphic components representing an average human thorax. It consists of real tissue equivalent materials to fulfill the requirements for dosimetric experiments and imaging purposes. The different parts of the torso (lungs, chest wall, and ribs) and the tumor can move independently. Simple regular movements, as well as more advanced patient-specific breathing cycles are feasible while a reproducible setup can be guaranteed. The phantom provides the flexibility to use different types of dosimetric devices and was designed in a way that it is robust, transportable and easy to handle. Tolerance levels and the reliability of the phantom setup were determined in combination with tests on motion accuracy and reproducibility by using infrared optical tracking technology. Different imaging was performed including positron emission tomography imaging, 4D computed tomography as well as real-time in-room imaging. The initial dosimetric benchmarking studies were performed in a photon beam where dose parameters are predictable and the dosimetric procedures well established.

EP-1268: Biological treatment response and hypoxia monitoring of cervix cancer using multiparametric 3T-MRI and 18F-FMISO

The purpose of this study was to assess characteristics, treatment outcomes and complications in patients with locally advanced or recurrent gynecological malignancies treated with interstitial brachytherapy using MUPIT. Materials and Methods: We performed a retrospective review of all patients with gynecological malignancies treated with MUPIT in a single institution between January 2005 and May 2014. Cases without data or follow up were excluded. Information recorded were demographic and clinic characteristics, previous use of RT (external or BT), dose rate of interstitial BT, local control rate, late toxicity and mortality rate. Categorical variables are presented as frequencies and proportions, and continuous variables as the mean, median, and range. Local recurrence-free survival (LRFS) and overall survival (OS) after MUPIT treatment were estimated using the Kaplan-Meier method. Results: Forty six patients were identified. The median age was 64 years (range, 28 85). Cervical and endometrial cancers were the most common primary site, with 20 and 16 cases respectively. The indications of interstitial BT were treatment of local recurrence (31), primary tumor (14) and metastases (1). Forty patients received external RT or BT before interstitial BT. High dose rate BT was used in 37 cases. Median LRFS was 76.2 months (CI 95% 61.6 90.7) and the median survival time was 82 months (CI 95% 67.5 96.5). There have been no cases of Grade IV late toxicity. Proctitis and pelvic pain were the most common grade III complications (4 patients). Conclusions: Interstitial BT using MUPIT applicator is an effective treatment which obtains high rates of local control despite the bad prognosis of pelvic recurrencies. Secondary effects are few, and manageable.

Strahlentherapieplanung mit der funktionellen MRT@@@Treatment planning with functional MRI

ZusammenfassungKlinisches/methodisches ProblemDie Strahlentherapieplanung mit der funktionellen Magnetresonanztomographie (fMRT) zielt auf eine Hochpräzisionsradiotherapie ab. Mit den modernen Technologien ist es möglich, die Strahlentherapie nahezu exakt an das Tumorvolumen anzupassen und dadurch das umliegende gesunde Gewebe zu schonen. Da die Strahlentherapie mit millimetergenauer Präzision appliziert werden kann, ist eine ebenso genaue Tumorabgrenzung essenziell.Radiologische StandardverfahrenIn der konventionellen Strahlentherapie ist die Durchführung einer Planungs-CT Standard. Bei vielen Tumorentitäten ist eine MRT notwendig, um den Tumor besser abgrenzen zu können. Die konventionelle Strahlentherapie behandelt den gesamten Tumor mit einer homogenen Strahlendosis.Methodische InnovationenIn der Tumorgenese spielen Vorgänge wie Zellproliferation, Hypoxie, Neoangiogenese, Perfusion und mikrovaskuläre Hyperpermeabilität eine wichtige Rolle. Die funktionelle MRT erlaubt es, eine Vielzahl dieser Prozesse durch unterschiedliche MR-Parameter darzustellen. Dadurch können die Volumina im Tumor identifiziert werden, die eine höhere Aggressivität besitzen, häufig radioresistent sind und so ein Rezidiv verursachen. Daher sollen sie mit einer höheren Strahlendosis behandelt werden. Diese Rationale, den Tumor inhomogen aufgrund seiner biologischen Charakteristika zu bestrahlen, bezeichnet man als „dose painting“.Bewertung„Dose painting“ ist technisch durchführbar und der klinische Vorteil ist durch Berücksichtigung der individuellen Tumorbiologie und der daraus folgend unterschiedlicher Therapieantwort abzuleiten. Durch eine an die Tumoreigenschaften angepasste Strahlentherapie werden bessere Therapieergebnisse erwartet.Empfehlung für die PraxisDie Implementation des „dose painting“ erfordert eine enge interdisziplinäre Kooperation zwischen Radioonkologen, Radiologen, Medizinphysikern und Strahlenbiologen.AbstractClinical/methodical issueThe aim of magnetic resonance imaging (MRI) guided radiotherapy is high precision in treatment delivery. With new developments it is possible to focus the high dose irradiation on the tumor while sparing the surrounding tissue. The achievements in precision of the treatment planning and delivery warrant equally precise tumor definition.Standard radiological methodsIn conventional radiation therapy it is necessary to carry out a planning computed tomography (CT). For many tumors there is also need for an additional morphological MRI because of more accurate tumor definition. In standard radiotherapy the tumor volume is irradiated with a homogeneous dose.Methodical innovationsThe aim of functional multiparametric MRI is to visualize and quantify biological, physiological and pathological processes at the cellular and molecular levels. Based on this information it is possible to elucidate tumor biology and identify subvolumes of more aggressive behavior. They are often radiotherapy-resistant, leading to tumor recurrence thus requiring further dose escalation. The concept of inhomogeneous tumor irradiation according to its biological behavior is called dose painting.PerformanceDose painting is technically feasible. The expected clinical benefit is motivated by selective treatment adaptations based on biological tumor characteristics. Tumors show variable response to therapy underlining the need for individual treatment plans. This approach may lead not only to higher local control but also to better sparing of normal surrounding tissue.AchievementsWith the clinical implementation of dose painting, improvements in the therapeutic outcome can be expected.Practical recommendationsDue to the existing technical challenges, extensive collaboration between radiation oncologists, radiologists, medical physicists and radiation biologists is needed.CLINICAL/METHODICAL ISSUE The aim of magnetic resonance imaging (MRI) guided radiotherapy is high precision in treatment delivery. With new developments it is possible to focus the high dose irradiation on the tumor while sparing the surrounding tissue. The achievements in precision of the treatment planning and delivery warrant equally precise tumor definition. STANDARD RADIOLOGICAL METHODS In conventional radiation therapy it is necessary to carry out a planning computed tomography (CT). For many tumors there is also need for an additional morphological MRI because of more accurate tumor definition. In standard radiotherapy the tumor volume is irradiated with a homogeneous dose. METHODICAL INNOVATIONS The aim of functional multiparametric MRI is to visualize and quantify biological, physiological and pathological processes at the cellular and molecular levels. Based on this information it is possible to elucidate tumor biology and identify subvolumes of more aggressive behavior. They are often radiotherapy-resistant, leading to tumor recurrence thus requiring further dose escalation. The concept of inhomogeneous tumor irradiation according to its biological behavior is called dose painting. PERFORMANCE Dose painting is technically feasible. The expected clinical benefit is motivated by selective treatment adaptations based on biological tumor characteristics. Tumors show variable response to therapy underlining the need for individual treatment plans. This approach may lead not only to higher local control but also to better sparing of normal surrounding tissue. ACHIEVEMENTS With the clinical implementation of dose painting, improvements in the therapeutic outcome can be expected. PRACTICAL RECOMMENDATIONS Due to the existing technical challenges, extensive collaboration between radiation oncologists, radiologists, medical physicists and radiation biologists is needed.

Treatment planning with functional MRI

ZusammenfassungKlinisches/methodisches ProblemDie Strahlentherapieplanung mit der funktionellen Magnetresonanztomographie (fMRT) zielt auf eine Hochpräzisionsradiotherapie ab. Mit den modernen Technologien ist es möglich, die Strahlentherapie nahezu exakt an das Tumorvolumen anzupassen und dadurch das umliegende gesunde Gewebe zu schonen. Da die Strahlentherapie mit millimetergenauer Präzision appliziert werden kann, ist eine ebenso genaue Tumorabgrenzung essenziell.Radiologische StandardverfahrenIn der konventionellen Strahlentherapie ist die Durchführung einer Planungs-CT Standard. Bei vielen Tumorentitäten ist eine MRT notwendig, um den Tumor besser abgrenzen zu können. Die konventionelle Strahlentherapie behandelt den gesamten Tumor mit einer homogenen Strahlendosis.Methodische InnovationenIn der Tumorgenese spielen Vorgänge wie Zellproliferation, Hypoxie, Neoangiogenese, Perfusion und mikrovaskuläre Hyperpermeabilität eine wichtige Rolle. Die funktionelle MRT erlaubt es, eine Vielzahl dieser Prozesse durch unterschiedliche MR-Parameter darzustellen. Dadurch können die Volumina im Tumor identifiziert werden, die eine höhere Aggressivität besitzen, häufig radioresistent sind und so ein Rezidiv verursachen. Daher sollen sie mit einer höheren Strahlendosis behandelt werden. Diese Rationale, den Tumor inhomogen aufgrund seiner biologischen Charakteristika zu bestrahlen, bezeichnet man als „dose painting“.Bewertung„Dose painting“ ist technisch durchführbar und der klinische Vorteil ist durch Berücksichtigung der individuellen Tumorbiologie und der daraus folgend unterschiedlicher Therapieantwort abzuleiten. Durch eine an die Tumoreigenschaften angepasste Strahlentherapie werden bessere Therapieergebnisse erwartet.Empfehlung für die PraxisDie Implementation des „dose painting“ erfordert eine enge interdisziplinäre Kooperation zwischen Radioonkologen, Radiologen, Medizinphysikern und Strahlenbiologen.AbstractClinical/methodical issueThe aim of magnetic resonance imaging (MRI) guided radiotherapy is high precision in treatment delivery. With new developments it is possible to focus the high dose irradiation on the tumor while sparing the surrounding tissue. The achievements in precision of the treatment planning and delivery warrant equally precise tumor definition.Standard radiological methodsIn conventional radiation therapy it is necessary to carry out a planning computed tomography (CT). For many tumors there is also need for an additional morphological MRI because of more accurate tumor definition. In standard radiotherapy the tumor volume is irradiated with a homogeneous dose.Methodical innovationsThe aim of functional multiparametric MRI is to visualize and quantify biological, physiological and pathological processes at the cellular and molecular levels. Based on this information it is possible to elucidate tumor biology and identify subvolumes of more aggressive behavior. They are often radiotherapy-resistant, leading to tumor recurrence thus requiring further dose escalation. The concept of inhomogeneous tumor irradiation according to its biological behavior is called dose painting.PerformanceDose painting is technically feasible. The expected clinical benefit is motivated by selective treatment adaptations based on biological tumor characteristics. Tumors show variable response to therapy underlining the need for individual treatment plans. This approach may lead not only to higher local control but also to better sparing of normal surrounding tissue.AchievementsWith the clinical implementation of dose painting, improvements in the therapeutic outcome can be expected.Practical recommendationsDue to the existing technical challenges, extensive collaboration between radiation oncologists, radiologists, medical physicists and radiation biologists is needed.CLINICAL/METHODICAL ISSUE The aim of magnetic resonance imaging (MRI) guided radiotherapy is high precision in treatment delivery. With new developments it is possible to focus the high dose irradiation on the tumor while sparing the surrounding tissue. The achievements in precision of the treatment planning and delivery warrant equally precise tumor definition. STANDARD RADIOLOGICAL METHODS In conventional radiation therapy it is necessary to carry out a planning computed tomography (CT). For many tumors there is also need for an additional morphological MRI because of more accurate tumor definition. In standard radiotherapy the tumor volume is irradiated with a homogeneous dose. METHODICAL INNOVATIONS The aim of functional multiparametric MRI is to visualize and quantify biological, physiological and pathological processes at the cellular and molecular levels. Based on this information it is possible to elucidate tumor biology and identify subvolumes of more aggressive behavior. They are often radiotherapy-resistant, leading to tumor recurrence thus requiring further dose escalation. The concept of inhomogeneous tumor irradiation according to its biological behavior is called dose painting. PERFORMANCE Dose painting is technically feasible. The expected clinical benefit is motivated by selective treatment adaptations based on biological tumor characteristics. Tumors show variable response to therapy underlining the need for individual treatment plans. This approach may lead not only to higher local control but also to better sparing of normal surrounding tissue. ACHIEVEMENTS With the clinical implementation of dose painting, improvements in the therapeutic outcome can be expected. PRACTICAL RECOMMENDATIONS Due to the existing technical challenges, extensive collaboration between radiation oncologists, radiologists, medical physicists and radiation biologists is needed.