Constrained treatment planning using sequential beam selection.

In this paper an algorithm is described for automated treatment plan generation. The algorithm aims at delivery of the prescribed dose to the target volume without violation of constraints for target, organs at risk and the surrounding normal tissue. Pre-calculated dose distributions for all candidate orientations are used as input. Treatment beams are selected in a sequential way. A score function designed for beam selection is used for the simultaneous selection of beam orientations and weights. In order to determine the optimum choice for the orientation and the corresponding weight of each new beam, the score function is first redefined to account for the dose distribution of the previously selected beams. Addition of more beams to the plan is stopped when the target dose is reached or when no additional dose can be delivered without violating a constraint. In the latter case the score function is modified by importance factor changes to enforce better sparing of the organ with the limiting constraint and the algorithm is run again.

Mixing intensity modulated electron and photon beams: combining a steep dose fall-off at depth with sharp and depth-independent penumbras and flat beam profiles.

For application in radiotherapy, intensity modulated high-energy electron and photon beams were mixed to create dose distributions that feature: (a) a steep dose fall-off at larger depths, similar to pure electron beams, (b) flat beam profiles and sharp and depth-independent beam penumbras, as in photon beams, and (c) a selectable skin dose that is lower than for pure electron beams. To determine the required electron and photon beam fluence profiles, an inverse treatment planning algorithm was used. Mixed beams were realized at a MM50 racetrack microtron (Scanditronix Medical AB, Sweden), and evaluated by the dose distributions measured in a water phantom. The multileaf collimator of the MM50 was used in a static mode to shape overlapping electron beam segments, and the dynamic multileaf collimation mode was used to realize the intensity modulated photon beam profiles. Examples of mixed beams were generated at electron energies of up to 40 MeV. The intensity modulated electron beam component consists of two overlapping concentric fields with optimized field sizes, yielding broad, fairly depth-independent overall beam penumbras. The matched intensity modulated photon beam component has high fluence peaks at the field edges to sharpen this penumbra. The combination of the electron and the photon beams yields dose distributions with the characteristics (a)-(c) mentioned above.

Role of DNA-PK subunits in radiosensitization by hyperthermia.

Thermal radiosensitization is thought to result from inhibition of repair of radiation-induced DNA damage, DNA double-strand breaks in particular. Since the DNA-dependent protein kinase (DNA-PK) complex plays a major role in the nonhomologous end-joining of DSBs, it has been suggested that inactivation of this complex as a whole or of its individual subunits by heat might be involved in radiosensitization by heat. To test this hypothesis further, the ability of heat to enhance the radiosensitivity of cells proficient or deficient in either Ku80 or the DNA-PK catalytic subunit (DNA-PKcs) was investigated. In cells of two Ku80-deficient and two DNA-PKcs-deficient and double-strand break-deficient cell lines, the extent of radiosensitization by heat was not reduced compared to that in both their isogenic gene-complemented counterparts as well as to that in their parental cells. Thus radiosensitization by hyperthermia can be obtained irrespective of the Ku80 or DNA-PKcs status in cells. Therefore, Ku80 or DNA-PKcs and hence nonhomologous DSB end-joining do not play a crucial role in the enhancement of cellular radiosensitivity by hyperthermia.

Pulsed-dose-rate and low-dose-rate brachytherapy: comparison of sparing effects in cells of a radiosensitive and a radioresistant cell line.

Pulsed-dose-rate regimens are an attractive alternative to continuous low-dose-rate brachytherapy. However, apart from data obtained from modeling, only a few in vitro results are available for comparing the biological effectiveness of both modalities. Cells of two human cell lines with survival fractions of 80% (RT112) and 10% (HX142) after a single dose of 2 Gy and with different halftimes for split-dose recovery and low-dose recovery were used. The cells were irradiated with a continuous low dose rate (80 cGy per hour) or with pulsed dose rate. Two different pulsed dose rates were tested: 4.25 Gy/h and 63 Gy/h. The effects of dose per pulse and the length of the interval between the pulses were investigated while keeping the overall treatment time constant. Survival after low-dose-rate irradiation was indistinguishable from that after pulses of 4.25 Gy/h in cells of both cell lines. Survival decreased with increasing dose per pulse. When the dose rate during the pulses was increased, survival decreased even further. This effect was most pronounced for the radiosensitive HX142 cells. In clinical pulsed-dose-rate brachytherapy, iridium sources move stepwise through the implant and deliver pulses at a high dose rate locally. These high-dose-rate pulses produce greater biological effectiveness compared to continuous low dose rate; this should be taken into account.

Radiation-induced bilateral optic neuropathy in cancer of the nasopharynx. Case failure analysis and a review of the literature.

CASE REPORT: A case history of unanticipated radiation-induced bilateral optic neuropathy, 18 months after induction chemotherapy and radiation therapy for a locally advanced nasopharyngeal carcinoma, is presented. Retrospective reanalysis of the radiation therapy technique, with emphasis on the doses received by the optic pathway structures, was performed. These re-calculations revealed unexpectedly high doses in the range 79 to 82 Gy (cumulative external and brachytherapy dose) at the level of the optic nerves, which explained the observed radiation injury. CONCLUSION: Routine implementation of computed tomography for 3D dose planning purposes is therefore advocated. Review of the current literature confirms the importance of 3D dose planning in avoiding this complication and high-lights the role of MRI in establishing the diagnosis of radiation-induced optic neuropathy.

Calculation of a pencil beam kernel from measured photon beam data.

Usually, pencil beam kernels for photon beam calculations are obtained by Monte Carlo calculations. In this paper, we present a method to derive a pencil beam kernel from measured beam data, i.e. central axis depth doses, phantom scatter factors and off-axis ratios. These data are usually available in a radiotherapy planning system. The differences from other similar works are: (a) the central part of the pencil beam is derived from the measured penumbra of large fields and (b) the dependence of the primary photon fluence on the depth caused by beam hardening in the phantom is taken into account. The calculated pencil beam will evidently be influenced by the methods and instruments used for measurement of the basic data set. This is of particular importance for an accurate prediction of the absorbed dose delivered by small fields. Comparisons with measurements show that the accuracy of the calculated dose distributions fits well in a 2% error interval in the open part of the field, and in a 2 mm isodose shift in the penumbra region.

Sharpening the penumbra of high energy electron beams with low weight narrow photon beams.

BACKGROUND AND PURPOSE: High energy (20-50 MeV) electron beams, available from the MM50 Racetrack Microtron, can be used for the treatment of deep-seated tumors. A disadvantage is the increasing penumbra width as a function of depth. By the addition of a narrow (typically 1 cm wide) photon beam near the field edge, the 50-90% penumbra width of the electron beam is reduced, yielding a significantly increased effective field size. MATERIALS AND METHODS: For rectangular electron beams in a water phantom (energies 25 and 40 MeV, field sizes 5 x 5-15 x 15 cm2) a computer program was used to optimize the photon beam parameters (position, weight and width) to obtain a combined beam with the sharpest penumbra at the optimization depth and a beam flatness within certain constraints. The study furthermore included penumbra sharpening of an irregular multileaf collimator-shaped field. RESULTS AND CONCLUSION: At optimization depths near R90, photon beam addition reduces the penumbra width by 40-50% (from 15-20 mm to 8-10 mm). Beam flatness at the optimization depth is within +/-5% and hot-spots are < or =120% for all depths. By the addition of narrow photon beams around the rectangular or irregular field, the electron field width can be reduced by 1-3 cm, while the effective field size is maintained.

DNA damage induction and tumour cell radiosensitivity: PFGE and halo measurements.

PURPOSE: To test whether induction of DNA damage is correlated with tumour-cell radiosensitivity. MATERIALS AND METHODS: Initial DNA damage caused by X-irradiation was measured in ten human tumour cell lines, which largely differed in radiosensitivity, using either the pulsed-field gel electrophoresis assay or the halo technique. RESULTS: None of the parameters of DNA damage correlated with any parameter of cellular radiosensitivity. This was not only true when the analysis was performed on all data but also when the analysis was performed after separating the cell lines into radioresistant and sensitive groups. Even when differences in chromosome number, ploidy and cell cycle distribution were taken into account, no significant correlations were obtained. CONCLUSIONS: Contrary to previous suggestions, differences in the number of double-strand breaks induced or chromatin-related 'presentation' of DNA lesions, measured by pulsed-field gel electrophoresis or halo respectively, are generally not the dominant factors determining tumour-cell radiosensitivity.

Calculation of absorbed dose distributions from dynamic wedges.

In radiotherapy with photon beams, the use of dynamic wedges, which are obtained by the movement of one of the jaws, offers an increasing flexibility relative to the traditional use of metal wedges. But it is a disadvantage for the measurement of absorbed dose distributions, because the absorbed dose at each measurement point can only be obtained after a complete movement of the jaw. Consequently, for radiotherapy planning, an algorithm should be available that does not require measurements for any specific dynamically wedged beam, but is based on only a modest number of measurements. In this paper, an algorithm for the calculation of the dose distribution from dynamic wedges is described. This algorithm uses the convolution of pencil beam kernels with a non-uniform field function. These pencil beam kernels are derived from empirical data resulting from measurements of the open beam only.

Hyperthermia may decrease the development of telangiectasia after radiotherapy.

CASE REPORT: A patient with recurrent breast cancer was reirradiated twice on adjacent fields with a time interval of 9 months. The first time she was treated with reirradiation alone, the second time with reirradiation plus hyperthermia. The reirradiation schedule for both fields was 8 x 4 Gy in 4 weeks. Both fields overlapped partly with the field of postoperative radiotherapy, which was applied 57 and 66 months earlier to a total dose of 40.5 Gy. RESULTS: During the 52 to 61 months follow-up, a remarkable difference in telangiectasia development, between the parts of the reirradiation fields overlapping with the primary radiotherapy field, became apparent. Telangiectasia was observed 9 months after treatment with reirradiation alone and progressed to confluent in 47 months after treatment. In the reirradiation plus hyperthermia area, the maximum observed telangiectasia was slight until 52 months after treatment. DISCUSSION: The difference in the development of telangiectasia between these fields cannot be explained by differences in any of the known radiation treatment related prognostic factors. A protective effect by hyperthermia has been suggested by Haveman and coworkers, who have shown experimentally that heat treatment leads to enhanced proliferation of endothelial cells, thereby inducing a fast repopulation and replacement of X-ray damaged cells. CONCLUSION: This difference in telangiectasia formation is an interesting observation. Whether such a protective effect of hyperthermia is of general relevance has to become clear from more extensive clinical studies.

Chromatin structure and cellular radiosensitivity: a comparison of two human tumour cell lines.

The role of variation in susceptibility to DNA damage induction was studied as a determinant for cellular radiosensitivity. Comparison of the radiosensitive HX142 and radioresistant RT112 cell lines previously revealed higher susceptibility to X-ray-induced DNA damage in the sensitive cell line using non-denaturing elution, but not when using alkaline unwinding. The present data also show that no difference in the amount of initial damage is seen when pulsed-field gel electrophoresis (PFGE) or comet analysis are used for DNA damage assessment. However, using the halo assay or a modified version of PFGE in which the higher DNA architecture remained partially intact, the radiosensitive cells showed steeper dose-response curves for initial DNA damage than the radioresistant cells. Analysis of the protein composition, of DNA-nucleoid structures revealed substantial differences when isolated from HX142 or RT112 cells. From our data, it is concluded that HX142 and RT112 differ in their structural organization of chromatin. As no differences in the kinetics of DNA damage rejoining were found, it is hypothesized that the same amount of lesions have a different impact in the two cell lines in that the 'presentation' of DNA damage alters the ratio of repairable to non-repairable DNA damage.

Calculation of the absorbed dose distribution due to irregularly shaped photon beams using pencil beam kernels derived form basic beam data.

In radiotherapy, accurately calculated dose distributions of irregularly shaped photon beams are needed. In this paper, an algorithm is presented which enables the calculation of dose distributions due to irregular fields using pencil beam kernels derived from simple basic beam data usually measured on treatment units, i.e. central axis depth-dose curves and profiles. The only extra data that are needed, and are not currently measured, is the phantom scatter factor curve at the reference depth. The algorithm has been developed as an extension to a previously developed algorithm for rectangular fields which is based on the Milan-Bentley storage model. In the case of an irregular field, the depth dose and the boundary function are computed by convolution of a field intensity function with pencil beam kernels. The depth dose is computed by using a 'scatter' kernel, which is derived from the stored depth-dose curves and from the phantom scatter factor curve. The boundary function is computed by using a 'boundary' kernel, which is derived from the boundary profile of a number of large square fields. Because of the simplicity of the data used and the underlying concepts, which for instance do not separate the head scatter from the primary beam, this algorithm presents some shortcomings. On the other hand, this simplicity is also of great advantage and the inaccuracy is acceptable for most clinical situations.

Primary structure and phylogeny of the Calvin cycle enzymes transketolase and fructosebisphosphate aldolase of Xanthobacter flavus.

Xanthobacter flavus, a gram-negative facultatively autotrophic bacterium, employs the Calvin cycle for the fixation of carbon dioxide. Cells grown under autotrophic growth conditions possess an Fe(2+)-dependent fructosebisphosphate (FBP) aldolase (class II) in addition to a class I FBP aldolase. By nucleotide sequencing and heterologous expression in Escherichia coli, genes encoding transketolase (EC 2.2.1.1.; CbbT) and class II FBP aldolase (EC 4.1.2.13; CbbA) were identified. A partial open reading frame encoding a protein similar to pentose-5-phosphate 3-epimerase was identified downstream from cbbA. A phylogenetic tree of transketolase proteins displays a conventional branching order. However, the class II FBP aldolase protein from X. flavus is only distantly related to that of E. coli. The autotrophic FBP aldolase proteins from X. flavus, Alcaligenes eutrophus, and Rhodobacter sphaeroides form a tight cluster, with the proteins from gram-positive bacteria as the closest relatives.

Radiation induced DNA damage and damage repair in three human tumour cell lines.

Three human tumour cell lines (HX142, RT112 and MGH-U1) with different radiosensitivities were tested for differences in the rate and/or extent of DNA unwinding in alkali as well as for differences in the induction of DNA double strand breaks by means of the pulsed field gel electrophoresis, after X-irradiation. Unlike that which has been found using the non-denaturing filter elution technique (NDE, McMillan et al., 1990), no differences in initial DNA damage (the extent of alkaline unwinding and the induction of double strand breaks) were found for the three cell lines. These data suggest that rather than a different number of DNA lesions per Da per Gy between these cell lines, structural differences in chromatin structure (related to radiosensitivity) might impair the detectability of lesions in some assays like the NDE. The nature of such structure differences remains unclear. However, the differences did not affect alkaline unwinding profiles, as all three cell lines showed identical rates of DNA unwinding after exposure to X-rays. Furthermore, the three cell lines did not show significant differences in the kinetics of DNA strand break rejoining nor in the amounts of damage remaining after 24 h repair. The results obtained in this study, together with other findings, suggest that the three cell lines may differ in their 'presentation' of DNA damage.

Calculation models for determining the absorbed dose in water phantoms in off-axis planes of rectangular fields of open and wedged photon beams.

Beam models are proposed for the calculation of the dose in off-axis planes of rectangular photon fields, when the data set used in the treatment planning system is based on the simple storage model of Milan and Bentley. For open beams the model separates the off-axis ratio into an envelope profile and two boundary profiles. The envelope profile gives the field intensity of the maximal position of the jaws and has rotational symmetry. The boundary profiles describe the boundaries of the field actually formed by the jaws. In the case of a wedged beam, the model also separates the off-axis ratio into envelope profiles and boundary profiles. To determine these profiles for the non-wedge direction from open beam profiles, the wedge thickness is converted to an equivalent water thickness. In the case of an asymmetric field, the boundary profiles are shifted to the field centre. Results of calculation with these models have been compared with measurements and the simple multiplication of profiles, which has often been used with the Milan-Bentley model. The new models agree within a few per cent with the measurements and are a great improvement compared to the simple multiplication of profiles.

Possible leakage radiation during malfunctioning of a Sagittaire accelerator.

A non-fatal accident with a CGR-Sagittaire accelerator in the Dr Daniel den Hoed Cancer Center (DDHCC) in Rotterdam in 1988 is described. In a period with frequently occurring technical problems, a patient, undergoing fractionated treatment at this accelerator for prostatic cancer, developed severe skin reactions on the right half ventral part of thorax, head and upper arm. The skin reactions suggested an irradiation with a dose of up to 10-20 Gy, so it was likely that a radiation accident had occurred caused by leakage radiation. A number of experiments were performed in attempting to explain the estimated large dose rates of leakage radiation. Under rather extreme malfunctioning conditions, a high leakage dose rate (4 Gy/min) could be obtained during therapy use. This condition might have occurred during this period of technical difficulty.

Improvement of depth dose distributions by addition of small doses from laterally incident beams.

A three beam irradiation technique is described, in which two beams add a relatively small amount of dose to the depth dose distribution of another beam. The result is a nearly flat depth dose distribution on the interval from the surface to an arbitrarily chosen depth and a steep dose decrease to a lower dose level beyond that interval. Dose addition to a single photon beam depth dose is mainly performed with adding wedged beams. The volume in which dose homogeneity is obtained, is independently influenced by the field shape of the adding beams and the field shape of the primary beam. The final distribution from dose addition to high energy electron beams generally has an increased therapeutic range. The use of photon wedged beams is less suitable to simultaneously increase the therapeutic range and the steepness of the depth dose decrease in these cases. The properties of the derived dose distributions and the influence of some variables are discussed.

Obliquely incident electron beams for irradiation of the internal mammary lymph nodes.

For irradiation of the internal mammary lymph nodes, together with irradiation of the breast, a number of more or less standardised techniques are used. Regarding some disadvantages of these techniques, a modified method is discussed, that uses an obliquely incident electron beam for the mammary lymph node irradiation. Dose distributions of obliquely incident electron beams are measured and compared with the results of a treatment planning program. A procedure to match this obliquely incident beam to the adjacent tangential photon beams, that irradiate the breast, is described and the resulting dose distribution is compared with a standard technique. Applications with this technique and its usefulness are discussed.