Validation of dose painting of lung tumours using alanine/EPR dosimetry.

Biologic image guided radiotherapy (RT) with escalated doses to tumour sub volumes challenges today's RT dose planning and delivery systems. In this phantom study, we verify the capability of a clinical dose planning and delivery system to deliver an 18F-FDG-PET based dose painted treatment plan to a lung tumour. Furthermore, we estimate the uncertainties of the dose painted treatment compared to conventional RT plans. An anthropomorphic thorax phantom of polystyrene and polyurethane was constructed based on CT images of a lung cancer patient. 101 EPR/alanine dosimeters were placed in separate cavities within the phantom. IMRT and VMAT plans were generated in Eclipse (version 10.0, Analytical Anisotropic Algorithm version 10.2.28, Varian Medical Systems, Inc.) for 6 and 15 MV photons, based on 18F-FDG-PET/CT images of the patient. A boost dose of 3.8 Gy/fraction was given to the 18F-FDG-avid region (biological planning volume; BTV), whereas 3.1 Gy/fraction was planned to the planning target volume (PTV, excluding the BTV). For the homogenous plans, 3.2 Gy/fraction was given to the PTV. Irradiation of the phantom was carried out at a Varian Trilogy linear accelerator (Varian Medical Systems, Inc.). Uncertainties involved in treatment planning and delivery were estimated from portal dosimetry gamma evaluation. Measured and calculated doses were compared by Bland-Altmann analysis. For all treatment plans, all dose-volume objectives could be achieved in the treatment planning system. The mean absolute differences between calculated and measured doses were small (<0.1 Gy) for BTV, PTV-BTV, lung and soft tissue. The estimated uncertainty of the planned doses was less than 3% for all plans, whereas the estimated uncertainty in the measured doses was less 2.3%. Our results show that planning and delivery of dose escalated lung cancer treatment on a clinical dose planning and delivery system has high dosimetric accuracy. The uncertainties associated with the dose escalated treatment plans are comparable to the conventional plans.

Biologic targets identified from dynamic 18FDG-PET and implications for image-guided therapy.

PURPOSE: The outcome of biologic image-guided radiotherapy depends on the definition of the biologic target. The purpose of the current work was to extract hyperperfused and hypermetabolic regions from dynamic positron emission tomography (D-PET) images, to dose escalate either region and to discuss implications of such image guided strategies. METHODS: Eleven patients with soft tissue sarcomas were investigated with D-PET. The images were analyzed using a two-compartment model producing parametric maps of perfusion and metabolic rate. The two image series were segmented and exported to a treatment planning system, and biological target volumes BTVper and BTVmet (perfusion and metabolism, respectively) were generated. Dice's similarity coefficient was used to compare the two biologic targets. Intensity-modulated radiation therapy (IMRT) plans were generated for a dose painting by contours regime, where planning target volume (PTV) was planned to 60 Gy and BTV to 70 Gy. Thus, two separate plans were created for each patient with dose escalation of either BTVper or BTVmet. RESULTS: BTVper was somewhat smaller than BTVmet (209 ± 170 cm(3) against 243 ± 143 cm(3), respectively; population-based mean and s.d.). Dice's coefficient depended on the applied margin, and was 0.72 ± 0.10 for a margin of 10 mm. Boosting BTVper resulted in mean dose of 69 ± 1.0 Gy to this region, while BTVmet received 67 ± 3.2 Gy. Boosting BTVmet gave smaller dose differences between the respective non-boost DVHs (such as D98). CONCLUSIONS: Dose escalation of one of the BTVs results in a partial dose escalation of the other BTV as well. If tumor aggressiveness is equally pronounced in hyperperfused and hypermetabolic regions, this should be taken into account in the treatment planning.

Functional imaging to monitor vascular and metabolic response in canine head and neck tumors during fractionated radiotherapy.

Radiotherapy causes alterations in tumor biology, and non-invasive early assessment of such alterations may become useful for identifying treatment resistant disease. The purpose of the current work is to assess changes in vascular and metabolic features derived from functional imaging of canine head and neck tumors during fractionated radiotherapy. Material and methods. Three dogs with spontaneous head and neck tumors received intensity-modulated radiotherapy (IMRT). Contrast-enhanced cone beam computed tomography (CE-CBCT) at the treatment unit was performed at five treatment fractions. Dynamic (18)FDG-PET (D-PET) was performed prior to the start of radiotherapy, at mid-treatment and at 3-12 weeks after the completion of treatment. Tumor contrast enhancement in the CE-CBCT images was used as a surrogate for tumor vasculature. Vascular and metabolic tumor parameters were further obtained from the D-PET images. Changes in these tumor parameters were assessed, with emphasis on intra-tumoral distributions. Results. For all three patients, metabolic imaging parameters obtained from D-PET decreased from the pre- to the inter-therapy session. Correspondingly, for two of three patients, vascular imaging parameters obtained from both CE-CBCT and D-PET increased. Only one of the tumors showed a clear metabolic response after therapy. No systematic changes in the intra-tumor heterogeneity in the imaging parameters were found. Conclusion. Changes in vascular and metabolic parameters could be detected by the current functional imaging methods. Vascular tumor features from CE-CBCT and D-PET corresponded well. CE-CBCT is a potential method for easy response assessment when the patient is at the treatment unit.

Quantitative dynamic ¹8FDG-PET and tracer kinetic analysis of soft tissue sarcomas.

PURPOSE: To study soft tissue sarcomas using dynamic positron emission tomography (PET) with the glucose analog tracer [(18)F]fluoro-2-deoxy-D-glucose ((18)FDG), to investigate correlations between derived PET image parameters and clinical characteristics, and to discuss implications of dynamic PET acquisition (D-PET). MATERIAL AND METHODS: D-PET images of 11 patients with soft tissue sarcomas were analyzed voxel-by-voxel using a compartment tracer kinetic model providing estimates of transfer rates between the vascular, non-metabolized, and metabolized compartments. Furthermore, standard uptake values (SUVs) in the early (2 min p.i.; SUVE) and late (45 min p.i.; SUVL) phases of the PET acquisition were obtained. The derived transfer rates K1, k2 and k3, along with the metabolic rate of (18)FDG (MRFDG) and the vascular fraction νp, was fused with the computed tomography (CT) images for visual interpretation. Correlations between D-PET imaging parameters and clinical parameters, i.e. tumor size, grade and clinical status, were calculated with a significance level of 0.05. RESULTS: The temporal uptake pattern of (18)FDG in the tumor varied considerably from patient to patient. SUVE peak was higher than SUVL peak for four patients. The images of the rate constants showed a systematic pattern, often with elevated intensity in the tumors compared to surrounding tissue. Significant correlations were found between SUVE/L and some of the rate parameters. CONCLUSIONS: Dynamic (18)FDG-PET may provide additional valuable information on soft tissue sarcomas not obtainable from conventional (18)FDG-PET. The prognostic role of dynamic imaging should be investigated.

Spatiotemporal analysis of tumor uptake patterns in dynamic (18)FDG-PET and dynamic contrast enhanced CT.

BACKGROUND: Molecular and functional imaging techniques such as dynamic positron emission tomography (DPET) and dynamic contrast enhanced computed tomography (DCECT) may provide improved characterization of tumors compared to conventional anatomic imaging. The purpose of the current work was to compare spatiotemporal uptake patterns in DPET and DCECT images. MATERIALS AND METHODS: A PET/CT protocol comprising DCECT with an iodine based contrast agent and DPET with (18)F-fluorodeoxyglucose was set up. The imaging protocol was used for examination of three dogs with spontaneous tumors of the head and neck at sessions prior to and after fractionated radiotherapy. Software tools were developed for downsampling the DCECT image series to the PET image dimensions, for segmentation of tracer uptake pattern in the tumors and for spatiotemporal correlation analysis of DCECT and DPET images. RESULTS: DCECT images evaluated one minute post injection qualitatively resembled the DPET images at most imaging sessions. Segmentation by region growing gave similar tumor extensions in DCECT and DPET images, with a median Dice similarity coefficient of 0.81. A relatively high correlation (median 0.85) was found between temporal tumor uptake patterns from DPET and DCECT. The heterogeneity in tumor uptake was not significantly different in the DPET and DCECT images. The median of the spatial correlation was 0.72. CONCLUSIONS: DCECT and DPET gave similar temporal wash-in characteristics, and the images also showed a relatively high spatial correlation. Hence, if the limited spatial resolution of DPET is considered adequate, a single DPET scan only for assessing both tumor perfusion and metabolic activity may be considered. However, further work on a larger number of cases is needed to verify the correlations observed in the present study.

Dynamic respiratory gated (18)FDG-PET of lung tumors - a feasibility study.

BACKGROUND: (18)FDG-PET/CT imaging is well established for diagnosis and staging of lung tumors. However, more detailed information regarding the distribution of FDG within the tumor, also as a function of time after injection may be relevant. In this study we explore the feasibility of a combined dynamic and respiratory gated (DR) PET protocol. MATERIAL AND METHODS: A DR FDG-PET protocol for a Siemens Biograph 16 PET/CT scanner was set up, allowing data acquisition from the time of FDG injection. Breath-hold (BH) respiratory gating was performed at four intervals over a total acquisition time of 50 minutes. Thus, the PET protocol provides both motion-free images and a spatiotemporal characterization of the glucose distribution in lung tumors. Software tools were developed in-house for tentative tumor segmentation and for extracting standard uptake values (SUVs) voxel by voxel, tumor volumes and SUV gradients in all directions. RESULTS: Four pilot patients have been investigated with the DR PET protocol. The procedure was well tolerated by the patients. The BH images appeared sharper, and SUV(max)/SUV(mean) was higher, compared to free breathing (FB) images. Also, SUV gradients in the periphery of the tumor in the BH images were in general greater than or equal to the gradients in the FB PET images. CONCLUSION: The DR FDG-PET protocol is feasible and the BH images have a superior quality compared to the FB images. The protocol may also provide information of relevance for radiotherapy planning and follow-up. A patient trial is needed for assessing the clinical value of the imaging protocol.

Dosimetric verification of biologically adapted IMRT.

PURPOSE: To investigate the delivery of biologically adapted high resolution intensity modulated radiotherapy (IMRT) to an anthropomorphic phantom, using dosimetric and radiobiologic measures. METHODS: A compartment based 3D hypoxia map of a highly heterogeneous tumor was imported into the CT planning basis of an anthropomorphic phantom. Biologically adapted IMRT was planned according to the corresponding 3D dose prescription map with elevated dose to the hypoxic regions. Three treatment fractions were delivered to the phantom by means of a conventional linear accelerator equipped with a high resolution micro multileaf collimator (mMLC). EDR2 radiographic films were positioned in two planes of the phantom during irradiation. Software was developed to analyze dose distributions from the prescription, dose plan, and films. Dose distributions were scored within each of four radiobiologic tumor compartments. The treatment effect in each tumor compartment was estimated as the equivalent uniform dose (EUD). A conventional gamma analysis was utilized for quantitative comparisons of planned and delivered dose distributions. RESULTS: The planned and delivered dose maps qualitatively resembled the prescribed dose map. The gamma analyzes showed that, on average for all films, more than 95% of the pixels within the tumor passed the 3%/2 mm criteria. For compartments with increasing degree of hypoxia and thereby increased prescribed dose, the planned and delivered EUDs were severely reduced compared to the prescription. The prescribed compartmental doses were met only for the most oxic compartment. The mean tumor dose as measured by the films was 6.6% lower than the corresponding planned dose. CONCLUSIONS: Biologically adapted radiotherapy may be delivered with high precision according to the dose plan. However, the large reduction in compartmental EUD values from prescribed to planned treatment indicated lower tumor effect than expected for such a treatment.

Adaptive radiotherapy based on contrast enhanced cone beam CT imaging.

Cone beam CT (CBCT) imaging has become an integral part of radiation therapy, with images typically used for offline or online patient setup corrections based on bony anatomy co-registration. Ideally, the co-registration should be based on tumor localization. However, soft tissue contrast in CBCT images may be limited. In the present work, contrast enhanced CBCT (CECBCT) images were used for tumor visualization and treatment adaptation. Material and methods. A spontaneous canine maxillary tumor was subjected to repeated cone beam CT imaging during fractionated radiotherapy (10 fractions in total). At five of the treatment fractions, CECBCT images, employing an iodinated contrast agent, were acquired, as well as pre-contrast CBCT images. The tumor was clearly visible in post-contrast minus pre-contrast subtraction images, and these contrast images were used to delineate gross tumor volumes. IMRT dose plans were subsequently generated. Four different strategies were explored: 1) fully adapted planning based on each CECBCT image series, 2) planning based on images acquired at the first treatment fraction and patient repositioning following bony anatomy co-registration, 3) as for 2), but with patient repositioning based on co-registering contrast images, and 4) a strategy with no patient repositioning or treatment adaptation. The equivalent uniform dose (EUD) and tumor control probability (TCP) calculations to estimate treatment outcome for each strategy. Results. Similar translation vectors were found when bony anatomy and contrast enhancement co-registration were compared. Strategy 1 gave EUDs closest to the prescription dose and the highest TCP. Strategies 2 and 3 gave EUDs and TCPs close to that of strategy 1, with strategy 3 being slightly better than strategy 2. Even greater benefits from strategies 1 and 3 are expected with increasing tumor movement or deformation during treatment. The non-adaptive strategy 4 was clearly inferior to all three adaptive strategies. Conclusion. CECBCT may prove useful for adaptive radiotherapy.

Influence of MLC leaf width on biologically adapted IMRT plans.

INTRODUCTION: High resolution beam delivery may be required for optimal biology-guided adaptive therapy. In this work, we have studied the influence of multi leaf collimator (MLC) leaf widths on the treatment outcome following adapted IMRT of a hypoxic tumour. MATERIAL AND METHODS: Dynamic contrast enhanced MR images of a dog with a spontaneous tumour in the nasal region were used to create a tentative hypoxia map following a previously published procedure. The hypoxia map was used as a basis for generating compartmental gross tumour volumes, which were utilised as planning structures in biologically adapted IMRT. Three different MLCs were employed in inverse treatment planning, with leaf widths of 2.5 mm, 5 mm and 10 mm. The number of treatment beams and the degree of step-and-shoot beam modulation were varied. By optimising the tumour control probability (TCP) function, optimal compartmental doses were derived and used as target doses in the inverse planning. Resulting IMRT dose distributions and dose volume histograms (DVHs) were exported and analysed, giving estimates of TCP and compartmental equivalent uniform doses (EUDs). The impact of patient setup accuracy was simulated. RESULTS: The MLC with the smallest leaf width (2.5 mm) consistently gave the highest TCPs and compartmental EUDs, assuming no setup error. The difference between this MLC and the 5 mm MLC was rather small, while the MLC with 10 mm leaf width gave considerably lower TCPs. When including random and systematic setup errors, errors larger than 5 mm gave only small differences between the MLC types. For setup errors larger than 7 mm no differences were found between non-uniform and uniform dose distributions. CONCLUSIONS: Biologically adapted radiotherapy may require MLCs with leaf widths smaller than 10 mm. However, for a high probability of cure it is crucial that accurate patient setup is ensured.

Feasibility of contrast-enhanced cone-beam CT for target localization and treatment monitoring.

A dog with a spontaneous maxillary tumour was given 40 Gy of fractionated radiotherapy. At five out of 10 fractions cone-beam CT (CBCT) imaging before and after administration of an iodinated contrast agent were performed. Contrast enhancement maps were overlaid on the pre-contrast CBCT images. The tumour was clearly visualized in the images thus produced.