Åste Søvik

Strategies for biologic image-guided dose escalation: a review.

There is increasing interest in how to incorporate functional and molecular information obtained by noninvasive, three-dimensional tumor imaging into radiotherapy. The key issues are to identify radioresistant regions that can be targeted for dose escalation, and to develop radiation dose prescription and delivery strategies providing optimal treatment for the individual patient. In the present work, we review the proposed strategies for biologic image-guided dose escalation with intensity-modulated radiation therapy. Biologic imaging modalities and the derived images are discussed, as are methods for target volume delineation. Different dose escalation strategies and techniques for treatment delivery and treatment plan evaluation are also addressed. Furthermore, we consider the need for response monitoring during treatment. We conclude with a summary of the current status of biologic image-based dose escalation and of areas where further work is needed for this strategy to become incorporated into clinical practice.

Optimization of tumour control probability in hypoxic tumours by radiation dose redistribution: a modelling study.

Tumour hypoxia is a known cause of clinical resistance to radiation therapy. The purpose of this work was to model the effects on tumour control probability (TCP) of selectively boosting the dose to hypoxic regions in a tumour, while keeping the mean tumour dose constant. A tumour model with a continuous oxygen distribution, incorporating pO(2) histograms published for head and neck patients, was developed. Temporal and spatial variations in the oxygen distribution, non-uniform cell density and cell proliferation during treatment were included in the tumour modelling. Non-uniform dose prescriptions were made based on a segmentation of the tumours into four compartments. The main findings were: (1) Dose redistribution considerably improved TCP for all tumours. (2) The effect on TCP depended on the degree of reoxygenation during treatment, with a maximum relative increase in TCP for tumours with poor or no reoxygenation. (3) Acute hypoxia reduced TCP moderately, while underdosing chronic hypoxic cells gave large reductions in TCP. (4) Restricted dose redistribution still gave a substantial increase in TCP as compared to uniform dose boosts. In conclusion, redistributing dose according to tumour oxygenation status might increase TCP when the tumour response to radiotherapy is limited by chronic hypoxia. This could potentially improve treatment outcome in a subpopulation of patients who respond poorly to conventional radiotherapy.

Adapting radiotherapy to hypoxic tumours

In the current work, the concepts of biologically adapted radiotherapy of hypoxic tumours in a framework encompassing functional tumour imaging, tumour control predictions, inverse treatment planning and intensity modulated radiotherapy (IMRT) were presented. Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) of a spontaneous sarcoma in the nasal region of a dog was employed. The tracer concentration in the tumour was assumed related to the oxygen tension and compared to Eppendorf histograph measurements. Based on the pO(2)-related images derived from the MR analysis, the tumour was divided into four compartments by a segmentation procedure. DICOM structure sets for IMRT planning could be derived thereof. In order to display the possible advantages of non-uniform tumour doses, dose redistribution among the four tumour compartments was introduced. The dose redistribution was constrained by keeping the average dose to the tumour equal to a conventional target dose. The compartmental doses yielding optimum tumour control probability (TCP) were used as input in an inverse planning system, where the planning basis was the pO(2)-related tumour images from the MR analysis. Uniform (conventional) and non-uniform IMRT plans were scored both physically and biologically. The consequences of random and systematic errors in the compartmental images were evaluated. The normalized frequency distributions of the tracer concentration and the pO(2) Eppendorf measurements were not significantly different. 28% of the tumour had, according to the MR analysis, pO(2) values of less than 5 mm Hg. The optimum TCP following a non-uniform dose prescription was about four times higher than that following a uniform dose prescription. The non-uniform IMRT dose distribution resulting from the inverse planning gave a three times higher TCP than that of the uniform distribution. The TCP and the dose-based plan quality depended on IMRT parameters defined in the inverse planning procedure (fields and step-and-shoot intensity levels). Simulated random and systematic errors in the pO(2)-related images reduced the TCP for the non-uniform dose prescription. In conclusion, improved tumour control of hypoxic tumours by dose redistribution may be expected following hypoxia imaging, tumour control predictions, inverse treatment planning and IMRT.

DCEMRI monitoring of canine tumors during fractionated radiotherapy.

Purpose. To monitor the contrast enhancement in spontaneous canine tumors during fractionated radiotherapy by Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCEMRI). Methods and material. Six dogs with tumors in the oral or nasal cavity received fractionated conformal radiotherapy with 54 Gy given in 18 fractions. T1 weighted DCE imaging was performed prior to each treatment fraction. The tumor was manually delineated in the MR images following every imaging session, and the time dependence of the Relative Signal Intensity (RSI) in the tumor was extracted voxel by voxel. RSI images at the time of maximum enhancement were generated, in addition to images of the initial slope of the RSI curves. The dependence of the median RSI and median slope in the tumor on the accumulated radiation dose was investigated, and images obtained at different treatment fraction were compared by correlation analysis. Results. Five of the six tumors regressed during treatment. The dose dependence of the RSI varied between the tumors, with some showing an increase and others a decrease in RSI with dose. This was also the case for the initial slope of the RSI curves. The correlation between images acquired before the first treatment fraction and subsequent fractions was in general low, and decreased significantly with accumulated radiation dose for five of six tumors. Conclusions. Large individual variations in the dose response of tumor contrast enhancement were found. Decreasing image correlation resulted both from tumor regression and intratumoral changes in the RSI distribution during treatment. These findings may have consequences for treatment design in biological image-guided radiotherapy.

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

Abstract 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 18F-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.

Influence of MLC leaf width on biologically adapted IMRT plans.

Abstract 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.

Adaptive radiotherapy based on contrast enhanced cone beam CT imaging

Abstract 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.

Adapting Biological Feedback in Radiotherapy

Recently, there has been much interest in how to use information on patient-specific tumor biology and normal tissue function to individualize cancer treatment. In radiation therapy, dose may be escalated to radioresistant regions within a tumor, or regions of particular functional importance in normal organs may be preferentially spared. However, tumor and normal tissue biology may change during treatment, and adaptation of therapy may be necessary to ensure that optimal therapy is delivered. Furthermore, changes in tumor and normal tissue biology during early treatment may be predictive for the outcome of radiotherapy, and this information could be used for individual adaptation of the remaining part of the treatment. In the present study, we address variations that may occur in tumor and normal tissue radiobiological properties during radiotherapy, and how these may be related to the response to treatment. Moreover, we discuss the criteria for when to adapt treatment and how this adaptation should be performed. Finally, we discuss to what degree biologically adapted radiotherapy may be expected to improve treatment outcome and which issues need to be resolved for this strategy to reach its full potential.

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.

DCEMRI of spontaneous canine tumors during fractionated radiotherapy: A pharmacokinetic analysis

PURPOSE To estimate pharmacokinetic parameters from dynamic contrast-enhanced magnetic resonance (DCEMR) images of spontaneous canine tumors taken during the course of fractionated radiotherapy, and to quantify treatment-induced changes in these parameters. MATERIALS AND METHODS Six dogs with tumors in the oral or nasal cavity received fractionated conformal radiotherapy with 54 Gy given in 18 fractions. T(1)-weighted DCEMR imaging was performed prior to each treatment fraction. Time-intensity curves in the tumor were extracted voxel-by-voxel, and were fitted to the Brix pharmacokinetic model. The dependence of the pharmacokinetic parameters on the accumulated radiation dose was calculated. RESULTS The Brix model reproduced the time-intensity curves well. A reduction in the k(ep) parameter with accumulated radiation dose was found for five (three significant) out of six cases, while the results for the A parameter were less consistent. Both pre-treatment k(ep) and the change in k(ep) with accumulated dose correlated significantly with tumor regression. CONCLUSIONS Pharmacokinetic parameters derived from DCEMR images taken during fractionated radiotherapy may predict response to radiotherapy. This may potentially impact on patient stratification and monitoring of treatment response for image-guided treatment strategies.