TP53 and the Ultimate Biological Optimization Steps of Curative Radiation Oncology.

The new biological interaction cross-section-based repairable-homologically repairable (RHR) damage formulation for radiation-induced cellular inactivation, repair, misrepair, and apoptosis was applied to optimize radiation therapy. This new formulation implies renewed thinking about biologically optimized radiation therapy, suggesting that most TP53 intact normal tissues are low-dose hypersensitive (LDHS) and low-dose apoptotic (LDA). This generates a fractionation window in LDHS normal tissues, indicating that the maximum dose to organs at risk should be ≤2.3 Gy/Fr, preferably of low LET. This calls for biologically optimized treatments using a few high tumor dose-intensity-modulated light ion beams, thereby avoiding secondary cancer risks and generating a real tumor cure without a caspase-3-induced accelerated tumor cell repopulation. Light ions with the lowest possible LET in normal tissues and high LET only in the tumor imply the use of the lightest ions, from lithium to boron. The high microscopic heterogeneity in the tumor will cause local microscopic cold spots; thus, in the last week of curative ion therapy, when there are few remaining viable tumor clonogens randomly spread in the target volume, the patient should preferably receive the last 10 GyE via low LET, ensuring perfect tumor coverage, a high cure probability, and a reduced risk for adverse normal tissue reactions. Interestingly, such an approach would also ensure a steeper rise in tumor cure probability and a higher complication-free cure, as the few remaining clonogens are often fairly well oxygenated, eliminating a shallower tumor response due to inherent ion beam heterogeneity. With the improved fractionation proposal, these approaches may improve the complication-free cure probability by about 10-25% or even more.

Dose prescription and treatment planning based on FMISO-PET hypoxia.

PURPOSE: The study presents the implementation of a novel method for incorporating hypoxia information from PET-CT imaging into treatment planning and estimates the efficiency of various optimization approaches. Its focuses on the feasibility of optimizing treatment plans based on the non-linear conversion of PET hypoxia images into radiosensitivity maps from the uptake properties of the tracers used. MATERIAL AND METHODS: PET hypoxia images of seven head-and-neck cancer patients were used to determine optimal dose distributions needed to counteract the radiation resistance associated with tumor hypoxia assuming various scenarios regarding the evolution of the hypoxic compartment during the treatment. A research planning system for advanced studies has been used to optimize IMRT plans based on hypoxia information from patient PET images. These resulting plans were compared in terms of target coverage for the same fulfilled constraints regarding the organs at risk. RESULTS: The results of a planning study indicated the clinical feasibility of the proposed method for treatment planning based on PET hypoxia. Antihypoxic strategies would lead to small improvements in all the patients, but higher effects are expected for the fraction of patients with hypoxic tumors. For these, individualization of the treatment based on hypoxia PET imaging could lead to improved treatment outcome while creating the premises for limiting the irradiation of the surrounding normal tissues. CONCLUSIONS: The proposed approach offers the possibility of improved treatment results as it takes into consideration the heterogeneity and the dynamics of the hypoxic regions. It also provides early identification of the clinical cases that might benefit from dose escalation as well as the cases that could benefit from other counter-hypoxic measures.

Quantifying Cellular Repair, Misrepair and Apoptosis Induced by Boron Ions, Gamma Rays and PRIMA-1 Using the RHR Formulation.

The recent interaction cross-section-based formulation for radiation-induced direct cellular inactivation, mild and severe sublethal damage, DNA-repair and cell survival have been developed to accurately describe cellular repair, misrepair and apoptosis in TP53 wild-type and mutant cells. The principal idea of this new non-homologous repairable-homologous repairable (RHR) damage formulation is to separately describe the mild damage that can be rapidly handled by the most basic repair processes including the non-homologous end joining (NHEJ), and more complex damage requiring longer repair times and high-fidelity homologous recombination (HR) repair. Taking the interaction between these two key mammalian DNA repair processes more accurately into account has significantly improved the method as indicated in the original publication. Based on the principal mechanisms of 7 repair and 8 misrepair processes presently derived, it has been possible to quite accurately describe the probability that some of these repair processes when unsuccessful can induce cellular apoptosis with increasing doses of γrays, boron ions and PRIMA-1. Interestingly, for all LETs studied (≈0.3-160 eV/nm) the increase in apoptosis saturates when the cell survival reaches about 10% and the fraction of un-hit cells is well below the 1% level. It is shown that most of the early cell kill for low-to-medium LETs are due to apoptosis since the cell survival as well as the non-apoptotic cells agree very well at low doses and other death processes dominate beyond D > 1 Gy. The low-dose apoptosis is due to the fact that the full activation of the checkpoint kinases ATM and Chk2 requires >8 and >18 DSBs per cell to phosphorylate p53 at serine 15 and 20. Therefore, DNA repair is not fully activated until well after 1/2 Gy, and the cellular response may be apoptotic by default before the low-dose hyper sensitivity (LDHS) is replaced by an increased radiation tolerance as the DNA repair processes get maximal efficiency. In effect, simultaneously explaining the LDHS and inverse dose rate phenomena. The partial contributions by the eight newly derived misrepair processes was determined so they together accurately described the experimental apoptosis induction data for γ rays and boron ions. Through these partial misrepair contributions it was possible to predict the apoptotic response based solely on carefully analyzed cell survival data, demonstrating the usefulness of an accurate DNA repair-based cell survival approach. The peak relative biological effectiveness (RBE) of the boron ions was 3.5 at 160 eV/nm whereas the analogous peak relative apoptotic effectiveness (RAE) was 3.4 but at 40 eV/nm indicating the clinical value of the lower LET light ions (15 ≤ LET ≤ 55 eV/nm, 2 ≤ Z ≤5) in therapeutic applications to maximize tumor apoptosis and senescence. The new survival expressions were also applied on mouse embryonic fibroblasts with key knocked-out repair genes, showing a good agreement between the principal non-homologous and homologous repair terms and also a reasonable prediction of the associated apoptotic induction. Finally, the formulation was used to estimate the increase in DNA repair and apoptotic response in combination with the mutant p53 reactivating compound PRIMA-1 and γ rays, indicating a 10-2 times increase in apoptosis with 5 µM of the compound reaching apoptosis levels not far from peak apoptosis boron ions in a TP53 mutant cell line. To utilize PRIMA-1 induced apoptosis and cellular sensitization for reactive oxygen species (ROS), concomitant biologically optimized radiation therapy is proposed to maximize the complication free tumor cure for the multitude of TP53 mutant tumors seen in the clinic. The experimental data also indicated the clinically very important high-absorbed dose ROS effect of PRIMA-1.

Fast IMRT with narrow high energy scanned photon beams.

PURPOSE: Since the first publications on intensity modulated radiation therapy (IMRT) in the early 1980s almost all efforts have been focused on fairly time consuming dynamic or segmental multileaf collimation. With narrow fast scanned photon beams, the flexibility and accuracy in beam shaping increases, not least in combination with fast penumbra trimming multileaf collimators. Previously, experiments have been performed with full range targets, generating a broad bremsstrahlung beam, in combination with multileaf collimators or material compensators. In the present publication, the first measurements with fast narrow high energy (50 MV) scanned photon beams are presented indicating an interesting performance increase even though some of the hardware used were suboptimal. METHODS: Inverse therapy planning was used to calculate optimal scanning patterns to generate dose distributions with interesting properties for fast IMRT. To fully utilize the dose distributional advantages with scanned beams, it is necessary to use narrow high energy beams from a thin bremsstrahlung target and a powerful purging magnet capable of deflecting the transmitted electron beam away from the generated photons onto a dedicated electron collector. During the present measurements the scanning system, purging magnet, and electron collimator in the treatment head of the MM50 racetrack accelerator was used with 3-6 mm thick bremsstrahlung targets of beryllium. The dose distributions were measured with diodes in water and with EDR2 film in PMMA. Monte Carlo simulations with GEANT4 were used to study the influence of the electrons transmitted through the target on the photon pencil beam kernel. RESULTS: The full width at half-maximum (FWHM) of the scanned photon beam was 34 mm measured at isocenter, below 9.5 cm of water, 1 m from the 3 mm Be bremsstrahlung target. To generate a homogeneous dose distribution in a 10 x 10 cm2 field, the authors used a spot matrix of 100 equal intensity beam spots resulting in a uniformity of collimated 80%-20% penumbra of 9 mm at a primary electron energy of 50 MeV. For the more complex cardioid shaped dose distribution, they used 270 spots, which at a pulse repetition frequency of 200 Hz is completed every 1.36 s. CONCLUSIONS: The present measurements indicate that the use of narrow scanned photon beams is a flexible and fast method to deliver advanced intensity modulated beams. Fast scanned photon IMRT should, therefore, be a very interesting modality in the delivery of biologically optimized radiation therapy with the possibility for in vivo treatment verification with PET-CT imaging.

A systems biology approach to radiation therapy optimization.

During the last 20 years, the field of cellular and not least molecular radiation biology has been developed substantially and can today describe the response of heterogeneous tumors and organized normal tissues to radiation therapy quite well. An increased understanding of the sub-cellular and molecular response is leading to a more general systems biological approach to radiation therapy and treatment optimization. It is interesting that most of the characteristics of the tissue infrastructure, such as the vascular system and the degree of hypoxia, have to be considered to get an accurate description of tumor and normal tissue responses to ionizing radiation. In the limited space available, only a brief description of some of the most important concepts and processes is possible, starting from the key functional genomics pathways of the cell that are not only responsible for tumor development but also responsible for the response of the cells to radiation therapy. The key mechanisms for cellular damage and damage repair are described. It is further more discussed how these processes can be brought to inactivate the tumor without severely damaging surrounding normal tissues using suitable radiation modalities like intensity-modulated radiation therapy (IMRT) or light ions. The use of such methods may lead to a truly scientific approach to radiation therapy optimization, particularly when invivo predictive assays of radiation responsiveness becomes clinically available at a larger scale. Brief examples of the efficiency of IMRT are also given showing how sensitive normal tissues can be spared at the same time as highly curative doses are delivered to a tumor that is often radiation resistant and located near organs at risk. This new approach maximizes the probability to eradicate the tumor, while at the same time, adverse reactions in sensitive normal tissues are as far as possible minimized using IMRT with photons and light ions.

A DNA Repair-Based Model of Cell Survival with Important Clinical Consequences.

This work provides a description of a new interaction, cross-section-based model for radiation-induced cellular inactivation, sublethal damage, DNA repair and cell survival, with the ability to more accurately elucidate different radiation-response phenomena. The principal goal of this work is to describe the damage-induction cross sections, as well as repair and survival, as Poisson processes with two main types of damage: mild damage that can be rapidly handled by the most basic repair processes; and more complex damage requiring longer repair times and the high-fidelity homologous recombination (HR) repair process to ensure accuracy and safety in the survival. This work is unique in its use of Poisson statistics to quantify the main repairable cell compartments that are exposed to simple and more complex sublethal hits, the cross section of which determines what is homologically and non-homologically repairable. The new method is applied to central radiation damage and survival data, such as in vitro cellular repair and survival with key DNA repair genes knocked out, low-dose hypersensitivity (LDHS), change in survival over the cell cycle, and variation with linear energy transfer (LET) for densely ionizing ions, all results supporting our basic assumptions. Among the results, it was shown that less than 1% of the simple DSBs are lethal at approximately 2 Gy and below for sparsely ionizing radiations, but their δ-electron track ends of between 1.5 and 0.5 keV can deliver 0.5 MGy to a few hundred nm3 volumes, mainly due to multiple scatter detours and multiple secondary electrons. They can cause dual double-strand breaks (DSBs) on the periphery of nucleosomes that are the most common multiply damaged sites, with an average of 1-2 δ-electron track ends per cell nucleus at 2 Gy. LDHS is most likely due to the normal lack of fast, efficient repair of sublethal damage below approximately 0.5 Gy, and requires largely intact key DNA repair genes to achieve significant repair recovery at higher doses. The new repair model describes this phenomenon quite accurately. Cells with key non-homologous end joining (NHEJ) genes knocked-out, lose LDHS but provoke HR repair, and cells with HR genes knocked out may lose some LDHS, but provoke NHEJ repair. The DNA duplication during the S phase results in a direct doubling as well of the total and sublethal hit cross sections. For the lowest LET carbon ions, NHEJ is reduced to where it is almost eliminated at maximum relative biological effectiveness (RBE), while HR is induced more than by X rays, due to complex damage and misrepair of DSBs produced by numerous δ electrons. The use of a lower LET such as electrons or photons during the final week of radiation treatment may potentially maximize complication-free cure. Optimally-designed weekly fractionation schedules are proposed to maximize the DNA repair potential in normal tissues. Additionally, the optimal therapeutic ion species, LET, apoptosis and permanent growth arrest/senescence window is identified with helium, lithium and boron ions and LETs at approximately 15-55 eV/nm, to maximize these quantities in the tumor and minimize them in the normal tissues, resulting in a very high probability of complication-free cure.

Dose prescription and optimisation based on tumour hypoxia.

INTRODUCTION. Tumour hypoxia is an important factor that confers radioresistance to the affected cells and could thus decrease the tumour response to radiotherapy. The development of advanced imaging methods that quantify both the extent and the spatial distribution of the hypoxic regions has created the premises to devise therapies that target the hypoxic regions in the tumour. MATERIALS AND METHODS. The present study proposes an original method to prescribe objectively dose distributions that focus the radiation dose to the radioresistant tumour regions and could therefore spare adjacent normal tissues. The effectiveness of the method was tested for clinically relevant simulations of tumour hypoxia that take into consideration dynamics and heterogeneity of oxygenation. RESULTS AND DISCUSSION. The results have shown that highly heterogeneous dose distributions may lead to significant improvements of the outcome only for static oxygenations. In contrast, the proposed method that involves the segmentation of the dose distributions and the optimisation of the dose prescribed to each segment to account for local heterogeneity may lead to significantly improved local control for clinically-relevant patterns of oxygenation. The clinical applicability of the method is warranted by its relatively easy adaptation to functional imaging of tumour hypoxia obtained with markers with known uptake properties.

Quantifying tumour hypoxia by PET imaging--a theoretical analysis.

Information on tumour oxygenation could be obtained from various imaging methods, but the success of incorporating it into treatment planning depends on the accuracy of quantifying it. This study presents a theoretical analysis of the efficiency of measuring tumour hypoxia by PET imaging. Tissue oxygenations were calculated for ranges of biologically relevant physiological parameters and were then used to simulate PET images for markers with different uptake characteristics. The resulting images were used to calculate dose distributions that could lead to predefined tumour control levels. The results have shown that quantification of tumour hypoxia with PET may lead to different values according to the tracer used and the tumour site investigated. This would in turn be reflected into the dose distributions recommended by the optimisation algorithms. However, irrespective of marker-specific differences, focusing the radiation dose to the hypoxic areas appears to reduce the average tumour dose needed to achieve a certain control level.

Radiation-Induced Chromosomal Breaks may be DNA Repair Fragile Sites with Larger-scale Correlations to Eight Double-Strand-Break Related Data Sets over the Human Genome.

In this work, we compared the genomic distribution of common radiation-induced chromosomal breaks to eight different data sets covering the whole human genome. Sites with a high probability of chromatid breakage after exposure to low and high ionization density radiations were often located inside common and rare fragile sites, indicating that they may be a new and more local type of DNA repair-related fragility. Breaks in specific chromosome bands after acute exposure to oil and benzene also showed strong correlation with these sites and fragile sites. In addition, close correlation was found with cytologically detected chiasma and MLH1 immunofluorescence sites and with the HapMap recombination density distributions. Also, of interest, copy number changes occurred predominantly at radiation-induced breaks and fragile sites, at least for breast cancers with poor prognosis, and they decreased weakly but significantly in regions with increasing recombination and CpG density. An increased CpG density is linked to regions of high gene density to secure high-fidelity reproduction and survival. To minimize cancer induction, cancer-related genes are often located in regions of decreased recombination density and/or higher-than-average CpG density. It is compelling that all these data sets were influenced by the cells' handling of double-strand breaks and, more generally, DNA damage on its genome. In fact, the DNA repair genes systematically avoid regions with a high recombination density, as they need to be intact to accurately handle repairable DNA lesions.

Radial secondary electron dose profiles and biological effects in light-ion beams based on analytical and Monte Carlo calculations using distorted wave cross sections.

To speed up dose calculation, an analytical pencil-beam method has been developed to calculate the mean radial dose distributions due to secondary electrons that are set in motion by light ions in water. For comparison, radial dose profiles calculated using a Monte Carlo technique have also been determined. An accurate comparison of the resulting radial dose profiles of the Bragg peak for (1)H(+), (4)He(2+) and (6)Li(3+) ions has been performed. The double differential cross sections for secondary electron production were calculated using the continuous distorted wave-eikonal initial state method (CDW-EIS). For the secondary electrons that are generated, the radial dose distribution for the analytical case is based on the generalized Gaussian pencil-beam method and the central axis depth-dose distributions are calculated using the Monte Carlo code PENELOPE. In the Monte Carlo case, the PENELOPE code was used to calculate the whole radial dose profile based on CDW data. The present pencil-beam and Monte Carlo calculations agree well at all radii. A radial dose profile that is shallower at small radii and steeper at large radii than the conventional 1/r(2) is clearly seen with both the Monte Carlo and pencil-beam methods. As expected, since the projectile velocities are the same, the dose profiles of Bragg-peak ions of 0.5 MeV (1)H(+), 2 MeV (4)He(2+) and 3 MeV (6)Li(3+) are almost the same, with about 30% more delta electrons in the sub keV range from (4)He(2+)and (6)Li(3+) compared to (1)H(+). A similar behavior is also seen for 1 MeV (1)H(+), 4 MeV (4)He(2+) and 6 MeV (6)Li(3+), all classically expected to have the same secondary electron cross sections. The results are promising and indicate a fast and accurate way of calculating the mean radial dose profile.

Energy-range relation and mean energy variation in therapeutic particle beams.

Analytical expressions for the mean energy and range of therapeutic light ion beams and low- and high-energy electrons have been derived, based on the energy dependence of their respective stopping powers. The new mean energy and range relations are power-law expressions relevant for light ion radiation therapy, and are based on measured practical ranges or known tabulated stopping powers and ranges for the relevant incident particle energies. A practical extrapolated range, Rp, for light ions was defined, similar to that of electrons, which is very closely related to the extrapolated range of the primary ions. A universal energy-range relation for light ions and electrons that is valid for all material mixtures and compounds has been developed. The new relation can be expressed in terms of the range for protons and alpha particles, and is found to agree closely with experimental data in low atomic number media and when the difference in the mean ionization energy is low. The variation of the mean energy with depth and the new energy-range relation are useful for accurate stopping power and mass scattering power calculations, as well as for general particle transport and dosimetry applications.

4D laser camera for accurate patient positioning, collision avoidance, image fusion and adaptive approaches during diagnostic and therapeutic procedures.

A four-dimensional (4D) laser camera (LC) has been developed for accurate patient imaging in diagnostic and therapeutic radiology. A complementary metal-oxide semiconductor camera images the intersection of a scanned fan shaped laser beam with the surface of the patient and allows real time recording of movements in a three-dimensional (3D) or four-dimensional (4D) format (3D +time). The LC system was first designed as an accurate patient setup tool during diagnostic and therapeutic applications but was found to be of much wider applicability as a general 4D photon "tag" for the surface of the patient in different clinical procedures. It is presently used as a 3D or 4D optical benchmark or tag for accurate delineation of the patient surface as demonstrated for patient auto setup, breathing and heart motion detection. Furthermore, its future potential applications in gating, adaptive therapy, 3D or 4D image fusion between most imaging modalities and image processing are discussed. It is shown that the LC system has a geometrical resolution of about 0, 1 mm and that the rigid body repositioning accuracy is about 0, 5 mm below 20 mm displacements, 1 mm below 40 mm and better than 2 mm at 70 mm. This indicates a slight need for repeated repositioning when the initial error is larger than about 50 mm. The positioning accuracy with standard patient setup procedures for prostate cancer at Karolinska was found to be about 5-6 mm when independently measured using the LC system. The system was found valuable for positron emission tomography-computed tomography (PET-CT) in vivo tumor and dose delivery imaging where it potentially may allow effective correction for breathing artifacts in 4D PET-CT and image fusion with lymph node atlases for accurate target volume definition in oncology. With a LC system in all imaging and radiation therapy rooms, auto setup during repeated diagnostic and therapeutic procedures may save around 5 min per session, increase accuracy and allow efficient image fusion between all imaging modalities employed.

Variation in radiation sensitivity and repair kinetics in different parts of the spinal cord.

BACKGROUND: The spinal cord, known for its strongly serial character and high sensitivity to radiation even when a small segment is irradiated, is one of the most critical organs at risk to be spared during radiation therapy. To compare the sensitivity of different parts of the spinal cord, data for radiation myelopathy have been used. MATERIAL AND METHODS: In the present study, the relative seriality model was fitted to two different datasets of clinical radiation myelitis concerning cervical spinal cord after treating 248 patients for head and neck cancer and thoracic spinal cord after treating 43 patients with lung carcinoma. The maximum likelihood method was applied to fit the clinical data. The model parameters and their 68% confidence intervals were calculated for each dataset. The alpha/beta ratio for the thoracic cord was also was also found to be 0.9 (0-3.0) Gy. RESULTS: The dose-response curve for the more sensitive cervical myelopathy is well described by the parameters D(50)=55.9 (54.8-57.1) Gy, gamma=6.9 (5.0-9.2), s=0.13 (0.07-0.24), whereas the thoracic myelopathy is described by the parameters D(50)=75.5 (70.5-80.8) Gy, gamma=1.1 (0.6-1.6), s=36 (3.3-infinity). DISCUSSION AND CONCLUSIONS: Large differences in radiation response between the cervical and thoracic region of spinal cord are thus observed: cervical myelopathy seems to be characterized by medium seriality, while thoracic spinal cord is characterized by a highly serial dose-response. The much steeper dose-response curve for cervical spinal cord myelopathy can be interpreted as a higher number of functional subunits consistent with a higher amount of white matter close to the brain.

The dose--response relation for rat spinal cord paralysis analyzed in terms of the effective size of the functional subunit.

Radiobiological models for estimating normal tissue complication probability (NTCP) are increasingly used in order to quantify or optimize the clinical outcome of radiation therapy. A good NTCP model should fulfill at least the following two requirements: (a) it should predict the sigmoid shape of the corresponding dose-response curve and (b) it should accurately describe the probability of a specified response for arbitrary non-uniform dose delivery for a given endpoint as accurately as possible, i.e. predict the volume dependence. In recent studies of the volume effect of a rat spinal cord after irradiation with narrow and broad proton beams the authors claim that none of the existing NTCP models is able to describe their results. Published experimental data have been used here to try to quantify the change in the effective dose (D(50)) causing 50% response for different field sizes. The present study was initiated to describe the induction of white matter necrosis in a rat spinal cord after irradiation with narrow proton beams in terms of the mean dose to the effective volume of the functional subunit (FSU). The physically delivered dose distribution was convolved with a function describing the effective size or, more accurately, the sensitivity distribution of the FSU to obtain the effective mean dose deposited in it. This procedure allows the determination of the mean D(50) value of the FSUs of a certain size which is of interest for example if the cell nucleus of the oligodendrocyte is the sensitive target. Using the least-squares method to compare the effective doses for different sizes of the functional subunits with the experimental data the best fit was obtained with a length of about 9 mm. For the non-uniform dose distributions an effective FSU length of 8 mm gave the optimal fit with the probit dose-response model. The method could also be used to interpret the so-called bath and shower experiments where the heterogeneous dose delivery was used in the convolution process. The assumption of an effective FSU size is consistent with most of the effects seen when different portions of the rat spinal cord are irradiated to different doses. The effective FSU length from these experiments is about 8.5 +/- 0.5 mm. This length could be interpreted as an effective size of the functional subunits in a rat spinal cord, where multiple myelin sheaths are connected by a single oligodendrocyte and repair is limited by the range of oligodendrocyte progenitor cell diffusion. It was even possible to suggest a more likely than uniform effective FSU sensitivity distribution from the experimental data.

Development of phase-contrast X-ray imaging techniques and potential medical applications.

A significant improvement over conventional attenuation-based X-ray imaging, which lacks contrast in small objects and soft biological tissues, is obtained by introducing phase-contrast imaging. As recently demonstrated, phase-contrast imaging is characterized by its extraordinary image quality, greatly enhanced contrast, and good soft tissue discrimination with very high spatial resolution down to the micron and even the sub-micron region. The rapid development of compact X-ray sources of high brightness, tuneability, and monochromaticity as well as high-resolution X-ray detectors with high quantum efficiency and improved computational methods is stimulating the development of a new generation of X-ray imaging systems for medical applications. The present paper reviews some intrinsic mechanisms, recent technical developments and potential medical applications of two-, three- and four-dimensional phase-contrast X-ray imaging. Challenging issues in current phase-contrast imaging techniques and key clinical applications are discussed and possible developments of future high-contrast and high spatial and temporal resolution medical X-ray imaging systems are outlined.

Depth absorbed dose and LET distributions of therapeutic 1H, 4He, 7Li, and 12C beams.

The depth absorbed dose and LET (linear energy transfer) distribution of different ions of clinical interest such as 1H, 4He, 7Li, and 12C ions have been investigated using the Monte Carlo code SHIELD-HIT. The energies of the projectiles correspond to ranges in water and soft tissue of approximately 260 mm. The depth dose distributions of the primary particles and their secondaries have been calculated and separated with regard to their low and high LET components. A LET value below 10 eV/nm can generally be regarded as low LET and sparsely ionizing like electrons and photons. The high LET region may be assumed to start at 20 eV/nm where on average two double-strand breaks can be formed when crossing the periphery of a nucleosome, even though strictly speaking the LET limits are not sharp and ought to vary with the charge and mass of the ion. At the Bragg peak of a monoenergetic high energy proton beam, less than 3% of the total absorbed dose is comprised of high LET components above 20 eV/nm. The high LET contribution to the total absorbed dose in the Bragg peak is significantly larger with increasing ion charge as a natural result of higher stopping power and lower range straggling. The fact that the range straggling and multiple scattering are reduced by half from hydrogen to helium increases the possibility to accurately deposit only the high LET component in the tumor with negligible dose to organs at risk. Therefore, the lateral penumbra is significantly improved and the higher dose gradients of 7Li and 12C ions both longitudinally and laterally will be of major advantage in biological optimized radiation therapy. With increasing charge of the ion, the high LET absorbed dose in the beam entrance and the plateau regions where healthy normal tissues are generally located is also increased. The dose distribution of the high LET components in the 7Li beam is only located around the Bragg peak, characterized by a Gaussian-type distribution. Furthermore, the secondary particles produced by high energy 7Li ions in tissuelike media have mainly low LET character both in front of and beyond the Bragg peak.

Design of a fast multileaf collimator for radiobiological optimized IMRT with scanned beams of photons, electrons, and light ions.

Intensity modulated radiation therapy is rapidly becoming the treatment of choice for most tumors with respect to minimizing damage to the normal tissues and maximizing tumor control. Today, intensity modulated beams are most commonly delivered using segmental multileaf collimation, although an increasing number of radiation therapy departments are employing dynamic multileaf collimation. The irradiation time using dynamic multileaf collimation depends strongly on the nature of the desired dose distribution, and it is difficult to reduce this time to less than the sum of the irradiation times for all individual peak heights using dynamic leaf collimation [Svensson et al., Phys. Med. Biol. 39, 37-61 (1994)]. Therefore, the intensity modulation will considerably increase the total treatment time. A more cost-effective procedure for rapid intensity modulation is using narrow scanned photon, electron, and light ion beams in combination with fast multileaf collimator penumbra trimming. With this approach, the irradiation time is largely independent of the complexity of the desired intensity distribution and, in the case of photon beams, may even be shorter than with uniform beams. The intensity modulation is achieved primarily by scanning of a narrow elementary photon pencil beam generated by directing a narrow well focused high energy electron beam onto a thin bremsstrahlung target. In the present study, the design of a fast low-weight multileaf collimator that is capable of further sharpening the penumbra at the edge of the elementary scanned beam has been simulated, in order to minimize the dose or radiation response of healthy tissues. In the case of photon beams, such a multileaf collimator can be placed relatively close to the bremsstrahlung target to minimize its size. It can also be flat and thin, i.e., only 15-25 mm thick in the direction of the beam with edges made of tungsten or preferably osmium to optimize the sharpening of the penumbra. The low height of the collimator will minimize edge scatter from glancing incidence. The major portions of the collimator leafs can then be made of steel or even aluminum, so that the total weight of the multileaf collimator will be as low as 10 kg, which may even allow high-speed collimation in real time in synchrony with organ movements. To demonstrate the efficiency of this collimator design in combination with pencil beam scanning, optimal radiobiological treatments of an advanced cervix cancer were simulated. Different geometrical collimator designs were tested for bremsstrahlung, electron, and light ion beams. With a 10 mm half-width elementary scanned photon beam and a steel collimator with tungsten edges, it was possible to make as effective treatments as obtained with intensity modulated beams of full resolution, i.e., here 5 mm resolution in the fluence map. In combination with narrow pencil beam scanning, such a collimator may provide ideal delivery of photons, electrons, or light ions for radiation therapy synchronized to breathing and other organ motions. These high-energy photon and light ion beams may allow three-dimensional in vivo verification of delivery and thereby clinical implementation of the BioArt approach using Biologically Optimized three-dimensional in vivo predictive Assay based adaptive Radiation Therapy [Brahme, Acta Oncol. 42, 123-126 (2003)].

The radiation response of heterogeneous tumors.

Heterogeneous tumors often have a wide spectrum of radiation sensitivities due to factors like their genetic make up, clonal distribution and degree of genetic instability, as well as gradients of oxygen and nutrients. Recent studies demonstrate that the radiation response of heterogeneous tumors can be rather well described by a single effective clonogen compartment when the dose-response relation at high doses is of main interest. When a correct description of the clonogen survival is important at both low and high doses, a description based on one sensitive and one resistant clonogen compartment will be necessary and generally sufficient and surprisingly accurate. Such a description is valuable for example when in vivo PET-CT data are acquired early in the treatment to predict the required curative radiation dose. Methods are given for derivation of the sensitive and resistant cell compartments based on clinically observed dose-response relations and the degree of hypoxia. Principal characteristics of heterogeneous tumors are derived, such as the dose D(t) describing the transition when sensitive cells are lost and resistant cells start to dominate the response resulting in a fast change in slope of the cell survival curve. Since the effective compartments are based on the whole spectrum of radiation resistance, they will take both low intermediate and high sensitivity values into account, thus providing an accurate description of the radiation response over the entire range of clinically relevant doses.

Three-dimensional atlas of lymph node topography based on the visible human data set.

Comprehensive atlases of lymph node topography are necessary tools to provide a detailed description of the lymphatic distribution in relation to other organs and structures. Despite the recent developments of atlases and guidelines focusing on definitions of lymphatic regions, a comprehensive and detailed description of the three-dimensional (3D) nodal distribution is lacking. This article describes a new 3D atlas of lymph node topography based on the digital images of the Visible Human Male Anatomical (VHMA) data set. About 1,200 lymph nodes were localized in the data set and their distribution was compared with data from current cross-sectional lymphatic atlases. The identified nodes were delineated and then labeled with different colors that corresponded to their anatomical locations. A series of 2D illustrations, showing discrete locations, description, and distribution of major lymph nodes, was compiled to form a cross-sectional atlas. The resultant contours of all localized nodes in the VHMA data set were superimposed to develop a volumetric model. A 3D reconstruction was generated for the lymph nodes and surrounding structures. The volumetric lymph node topography was also integrated into the existing VOXEL-MAN digital atlas to obtain an interactive and photo-realistic visualization of the lymph nodes showing their proximity to blood vessels and surrounding organs. The lymph node topography forms part of our whole body atlas database, which includes organs, definitions, and parameters that are related to radiation therapy. The lymph node topography atlas could be utilized for visualization and exploration of the 3D lymphatic distribution to assist in defining the target volume for treatment based on the lymphatic spread surrounding the primary tumor.

Effective beam directions using radiobiologically optimized IMRT of node positive breast cancer.

The purpose of this study was to investigate the optimal coplanar beam directions when treating an early breast cancer with locoregional lymphatic spread with a few radiobiologically optimized intensity modulated beams. Also to determine the increase in the probability of complication-free cure with the number of beam portals and the smallest number required to perform a close to optimal treatment for this tumour site. Four test patients with stage II left-sided breast cancer were studied with heart, lung and contralateral breast as principal organs at risk. The clinical target volume consisted of the breast tissue remaining after surgery, the axillary, the internal mammary as well as the supraclavicular lymph nodes. Through an exhaustive search of all possible beam directions the most effective coplanar beams with one to four intensity modulated photon beam portals were investigated. Comparisons with uniform beam treatment techniques and up to 12 intensity modulated beams were also made. The different plans were optimized using the probability of complication-free tumour cure, P(+), as biological objective function. When using two intensity modulated beam directions three major sets of suitable directions were identified denoted by A, P and T. A corresponds to an anterior oblique pair of beams around 25 degrees and 325 degrees , P is a perpendicular lateral pair at around 50 degrees and 130 degrees whereas T is a more conventional tangential pair at around 155 degrees and 300 degrees . Interestingly, these configurations identify simply three major effective beam directions namely at 30 degrees +/-20 degrees , 145 degrees +/-20 degrees and 310 degrees +/-15 degrees . For the three intensity modulated beam technique a combination of these three effective beam directions generally covered the global maximum of the probability of complication-free tumour control. The improvement in complication-free cure probability with two optimally selected intensity modulated beams is around 10% when compared to a uniform beam technique with three to four beam portals. This increase is mainly due to a reduction by almost 1% in the probability of injury to the heart and an increase of 6% in the probability of local tumour control. When three or four biologically optimized beam portals are used a further increase in the probability of complication-free cure of about 6% can often be obtained. This improvement is caused by a small decrease in the probability of injury to the heart, left lung and other surrounding normal tissue, as well as a slight further increase in the probability of tumour control. The increase in the treatment outcome is minimal when more than four intensity modulated beams are employed. A small increase in dose homogeneity in the target volume and a slight decrease in the normal tissue volume receiving high dose may be seen, but without appreciably improving the complication-free cure probability. For a stage II breast cancer, three and in more complex cases four optimally oriented beams are sufficient to reach close to the maximum probability of complication-free tumour control when biologically optimized intensity modulated dose delivery is used. Angle of incidence optimization may then be advantageous starting from the given most effective three beam directions.