Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions.

Light-ion radiation therapy against hypoxic tumors is highly curative due to reduced dependence on the presence of oxygen in the tumor at elevated linear energy transfer (LET) towards the Bragg peak. Clinical ion beams using spread-out Bragg peak (SOBP) are characterized by a wide spectrum of LET values. Accurate treatment optimization requires a method that can account for influence of the variation in response for a broad range of tumor hypoxia, absorbed doses and LETs. This paper presents a parameterization of the Repairable Conditionally-Repairable (RCR) cell survival model that can describe the survival of oxic and hypoxic cells over a wide range of LET values, and investigates the relationship between hypoxic radiation resistance and LET. The biological response model was tested by fitting cell survival data under oxic and anoxic conditions for V79 cells irradiated with LETs within the range of 30-500 keV/µm. The model provides good agreement with experimental cell survival data for the range of LET investigated, confirming the robustness of the parameterization method. This new version of the RCR model is suitable for describing the biological response of mixed populations of oxic and hypoxic cells and at the same time taking into account the distribution of doses and LETs in the incident beam and its variation with depth in tissue. The model offers a versatile tool for the selection of LET and dose required in the optimization of the therapeutic effect, without severely affecting normal tissue in realistic tumors presenting highly heterogeneous oxic and hypoxic regions.

A comparative analysis of radiobiological models for cell surviving fractions at high doses.

For many years the linear-quadratic (LQ) model has been widely used to describe the effects of total dose and dose per fraction at low-to-intermediate doses in conventional fractionated radiotherapy. Recent advances in stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) have increased the interest in finding a reliable cell survival model, which will be accurate at high doses, as well. Different models have been proposed for improving descriptions of high dose survival responses, such as the Universal Survival Curve (USC), the Kavanagh-Newman (KN) and several generalizations of the LQ model, e.g. the Linear-Quadratic-Linear (LQL) model and the Pade Linear Quadratic (PLQ) model. The purpose of the present study is to compare a number of models in order to find the best option(s) which could successfully be used as a fractionation correction method in SRT. In this work, six independent experimental data sets were used: CHOAA8 (Chinese hamster fibroblast), H460 (non-small cell lung cancer, NSLC), NCI-H841 (small cell lung cancer, SCLC), CP3 and DU145 (human prostate carcinoma cell lines) and U1690 (SCLC). By detailed comparisons with these measurements, the performance of nine different radiobiological models was examined for the entire dose range, including high doses beyond the shoulder of the survival curves. Using the computed and measured cell surviving fractions, comparison of the goodness-of-fit for all the models was performed by means of the reduced χ (2)-test with a 95% confidence interval. The obtained results indicate that models with dose-independent final slopes and extrapolation numbers generally represent better choices for SRT. This is especially important at high doses where the final slope and extrapolation numbers are presently found to play a major role. The PLQ, USC and LQL models have the least number of shortcomings at all doses. The extrapolation numbers and final slopes of these models do not depend on dose. Their asymptotes for the cell surviving fractions are exponentials at low as well as high doses, and this is in agreement with the behaviour of the corresponding experimental data. This is an important improvement over the LQ model which predicts a Gaussian at high doses. Overall and for the highlighted reasons, it was concluded that the PLQ, USC and LQL models are theoretically well-founded. They could prove useful compared to the other proposed radiobiological models in clinical applications for obtaining uniformly accurate cell surviving fractions encountered in stereotactic high-dose radiotherapy as well as at medium and low doses.

Production of clinically useful positron emitter beams during carbon ion deceleration.

In external beam radiation therapy, radioactive beams offer the best clinical solution to simultaneously treat and in vivo monitor the dose delivery and tumor response using PET or PET-CT imaging. However, difficulties mainly linked to the low production efficiency have so far limited their use. This study is devoted to the analysis of the production of high energy (11)C fragments, preferably by projectile fragmentation of a stable monodirectional and monoenergetic primary (12)C beam in different absorbing materials (decelerators) in order to identify the optimal elemental composition. The study was performed using the Monte Carlo code SHIELD-HIT07. The track length and fluence of generated secondary particles were scored in a uniform absorber of 300 cm length and 10 cm radius, divided into slices of 1 cm thickness. The (11)C fluence build-up and mean energy variation with increasing decelerator depth are presented. Furthermore, the fluence of the secondary (11)C beam was studied as a function of its mean energy and the corresponding remaining range in water. It is shown that the maximum (11)C fluence build-up is high in compounds where the fraction by weight of hydrogen is high, being the highest in liquid hydrogen. Furthermore, a cost effective alternative solution to the single medium initially envisaged is presented: a two-media decelerator that comprises a first liquid hydrogen section followed by a second decelerating section made of a hydrogen-rich material, such as polyethylene (C(2)H(4)). The purpose of the first section is to achieve a fast initial (11)C fluence build-up, while the second section is primarily designed to modulate the mean energy of the generated (11)C beam in order to reach the tumor depth. Finally, it was demonstrated that, if the intensity of the primary (12)C beam can be increased by an order of magnitude, a sufficient intensity of the secondary (11)C beam is achieved for therapy and subsequent therapeutic PET imaging sessions. Such an increase in the intensity might be easily achieved with a superconducting cyclotron.

Analytical description of the LET dependence of cell survival using the repairable-conditionally repairable damage model.

In light-ion radiation therapy, both the dose and the local energy spectrum, which is often characterized with the linear energy transfer (LET), must be considered. In treatment optimization, it is advantageous to use a radiobiological model that analytically accounts for both dose and LET for the ion type of interest. With such a model the biological effect can also be estimated for dose and LET combinations for which there are no observations in the underlying experimental data. In this study, the repairable-conditionally repairable (RCR) damage model was extended by expressing its parameters as functions of LET to provide a radiobiological model that accounts for both the dose and the LET for a given ion type and cell line. This LET-parameterized RCR model was fitted to published cell survival data for HSG and V79 cells irradiated with carbon ions and for T1 cells irradiated with helium ions. To test the robustness of the model, fittings to only a subset of the data were performed. Good agreement with the cell survival data was obtained, including survival data for LET values not used for model fitting, opening up the possibility of using the model in treatment planning for light ions.

Analytical theory for the fluence, planar fluence, energy fluence, planar energy fluence and absorbed dose of primary particles and their fragments in broad therapeutic light ion beams.

The purpose of the present work is to develop analytical expressions for the depth variation of the fluence, planar fluence, the energy fluence, planar energy fluence, the mean energy and absorbed dose of primary ions and their associated fragments in tissue-like media with ranges of clinical interest. The analytical expressions of the primary ions and associated fragments take into account nuclear interactions, energy losses, range straggling and multiple scattering. The analytical models of the radiation field quantities were compared with the results of the modified Monte Carlo (MC) code SHIELD-HIT(+). The results show that the shape of the depth absorbed dose distribution of the primary particles is characterized by an increasingly steep exponential fluence decrease with depth as the charge and atomic weight increase. This is accompanied by a compensating increased energy loss towards the Bragg peak as the charge of the ion increases. These largely compensating mechanisms are the main reason that the depth absorbed dose curve of all light ions is surprisingly similar. In addition, a rather uniform dose in the plateau region is obtained since the increasing fragment production almost precisely compensates the loss of primaries. The dominating light fragments such as protons and alpha particles are characterized by longer ranges than the primaries and their depth dose curves to some extent coincide well with the depth fluence curves due to a rather slow variation of mean stopping powers. In contrast, the heavier fragments are characterized by the build up of a slowing down spectrum similar to that of the primaries but with initially slightly shorter or longer ranges depending on their mass to atomic number ratio. The presented analytical theory for the light ion penetration in matter agree quite well with the MC and experimental data and may be very useful for fast analytical calculations of quantities like mean energy, fluence, energy fluence, absorbed dose, and LET.

An analytical model for light ion pencil beam dose distributions: multiple scattering of primary and secondary ions.

An analytical algorithm based on the generalized Fermi-Eyges theory, amended for multiple Coulomb scattering and energy loss straggling, is used for calculation of the dose distribution of light ion beams in water. Pencil beam energy deposition distributions are derived for light ions by weighting a Monte Carlo (MC) calculated planar integral dose distribution with analytically calculated multiple scattering and range straggling distributions. The planar integral dose distributions are calculated using the MC code SHIELD-HIT07, in which multiple scattering and energy loss straggling processes are excluded. The contribution from nuclear reactions is included in the MC calculations. Multiple scattering processes are calculated separately for primary and secondary ions and parameters of the initial angular and radial spreads, and the covariance of these are derived by a least-square parameterization of the SHIELD-HIT07 data. The results from this analytical algorithm are compared to pencil beam dose distributions obtained from SHIELD-HIT07, where all processes are included, as well as to experimental data. The presented analytical approach allows for the accurate calculation of the spatial energy deposition distributions of ions of atomic numbers Z = 1 - 8.

Design and characterization of a tissue-equivalent CVD-diamond detector for clinical dosimetry in high-energy photon beams.

New solid-state detectors, based on chemical vapour deposited (CVD) polycrystalline diamonds produced by hot-filament (HF) or microwave plasma (MW) assisted deposition methods, were constructed for radiation therapy dosimetry. Properties of diamond crystals, such as high radiation sensitivity, resistance to radiation damage and tissue-equivalence giving a low-energy dependence are very advantageous for clinical dosimetry. Therefore the encapsulation was specially designed for these detectors to have as little influence as possible on the radiation response. The prototypes were irradiated with use of a wide range of photon beam qualities ((60)Co gamma-rays, 6 and 18 MV X-rays). The radiation sensitivity varied considerably between samples deposited with HF (9 nC Gy(-1)mm(-3)) and MW (66 and 144 nC Gy(-1)mm(-3)) methods. For all detectors the leakage current was of the order of 10% of the radiation-induced current (bias voltage 100 V, dose rate 0.3 Gy/min). When irradiated with (60)Co gamma-rays, the detectors showed a dose-rate linearity with an exponential Delta parameter close to unity. However, a difference of 8% was found between Delta values for the different beam qualities. A small energy dependence was observed, for which the most probable sources are interface effects due to the silver electrodes and partly the geometry of the encapsulation which needs to be further optimized. Despite some limitations in the performance of present prototype detectors, with an improved CVD technique producing crystals of better electrical and dosimetric properties, and with a well-designed tissue-equivalent encapsulation, CVD-diamonds could serve as very good dosimeters for radiotherapy.

Development of dose delivery verification by PET imaging of photonuclear reactions following high energy photon therapy.

A method for dose delivery monitoring after high energy photon therapy has been investigated based on positron emission tomography (PET). The technique is based on the activation of body tissues by high energy bremsstrahlung beams, preferably with energies well above 20 MeV, resulting primarily in 11C and 15O but also 13N, all positron-emitting radionuclides produced by photoneutron reactions in the nuclei of 12C, 16O and 14N. A PMMA phantom and animal tissue, a frozen hind leg of a pig, were irradiated to 10 Gy and the induced positron activity distributions were measured off-line in a PET camera a couple of minutes after irradiation. The accelerator used was a Racetrack Microtron at the Karolinska University Hospital using 50 MV scanned photon beams. From photonuclear cross-section data integrated over the 50 MV photon fluence spectrum the predicted PET signal was calculated and compared with experimental measurements. Since measured PET images change with time post irradiation, as a result of the different decay times of the radionuclides, the signals from activated 12C, 16O and 14N within the irradiated volume could be separated from each other. Most information is obtained from the carbon and oxygen radionuclides which are the most abundant elements in soft tissue. The predicted and measured overall positron activities are almost equal (-3%) while the predicted activity originating from nitrogen is overestimated by almost a factor of two, possibly due to experimental noise. Based on the results obtained in this first feasibility study the great value of a combined radiotherapy-PET-CT unit is indicated in order to fully exploit the high activity signal from oxygen immediately after treatment and to avoid patient repositioning. With an RT-PET-CT unit a high signal could be collected even at a dose level of 2 Gy and the acquisition time for the PET could be reduced considerably. Real patient dose delivery verification by means of PET imaging seems to be applicable provided that biological transport processes such as capillary blood flow containing mobile 15O and 11C in the activated tissue volume can be accounted for.

Assessing the difference between planned and delivered intensity-modulated radiotherapy dose distributions based on radiobiological measures.

AIMS: Because of the highly conformal distributions that can be obtained with intensity-modulated radiotherapy (IMRT), any discrepancy between the intended and delivered distributions would probably affect the clinical outcome. Consequently, there is a need for a measure that would quantify those differences in terms of a change in the expected clinical outcome. MATERIALS AND METHODS: To evaluate such a measure, cancer of the cervix was used, where the bladder and rectum are proximal and partially overlapping with the internal target volume. A solid phantom simulating the pelvic anatomy was fabricated and a treatment plan was developed to deliver the prescribed dose to the phantom. The phantom was then irradiated with films positioned in several transverse planes. The racetrack microtron at 50 MV was used in the treatment planning and delivery processes. The dose distribution delivered was analysed based on the film measurements and compared against the treatment plan. The differences in the measurements were evaluated using both physical and biological criteria. Whereas the physical comparison of dose distributions can assess the geometric accuracy of delivery, it does not reflect the clinical effect of any measured dose discrepancies. RESULTS: It is shown how small inaccuracies in delivered dose can affect the treatment outcome in terms of complication-free tumour cure. CONCLUSIONS: With highly conformal IMRT, the accuracy of the patient set-up and treatment delivery are critical for the success of the treatment. A method is proposed to evaluate the precision of the delivered plan based on changes in complication and control rates as they relate to uncertainties in dose delivery.

Influence of electrodes on the photon energy deposition in CVD-diamond dosimeters studied with the Monte Carlo code PENELOPE.

A new dosimeter, based on chemical vapour deposited (CVD) diamond as the active detector material, is being developed for dosimetry in radiotherapeutic beams. CVD-diamond is a very interesting material, since its atomic composition is close to that of human tissue and in principle it can be designed to introduce negligible perturbations to the radiation field and the dose distribution in the phantom due to its small size. However, non-tissue-equivalent structural components, such as electrodes, wires and encapsulation, need to be carefully selected as they may induce severe fluence perturbation and angular dependence, resulting in erroneous dose readings. By introducing metallic electrodes on the diamond crystals, interface phenomena between high- and low-atomic-number materials are created. Depending on the direction of the radiation field, an increased or decreased detector signal may be obtained. The small dimensions of the CVD-diamond layer and electrodes (around 100 microm and smaller) imply a higher sensitivity to the lack of charged-particle equilibrium and may cause severe interface phenomena. In the present study, we investigate the variation of energy deposition in the diamond detector for different photon-beam qualities, electrode materials and geometric configurations using the Monte Carlo code PENELOPE. The prototype detector was produced from a 50 microm thick CVD-diamond layer with 0.2 microm thick silver electrodes on both sides. The mean absorbed dose to the detector's active volume was modified in the presence of the electrodes by 1.7%, 2.1%, 1.5%, 0.6% and 0.9% for 1.25 MeV monoenergetic photons, a complete (i.e. shielded) (60)Co photon source spectrum and 6, 18 and 50 MV bremsstrahlung spectra, respectively. The shift in mean absorbed dose increases with increasing atomic number and thickness of the electrodes, and diminishes with increasing thickness of the diamond layer. From a dosimetric point of view, graphite would be an almost perfect electrode material. This study shows that, for the considered therapeutic beam qualities, the perturbation of the detector signal due to charge-collecting graphite electrodes of thicknesses between 0.1 and 700 microm is negligible within the calculation uncertainty of 0.2%.

Influence of multiple scattering and energy loss straggling on the absorbed dose distributions of therapeutic light ion beams: I. Analytical pencil beam model.

The lateral and longitudinal distributions of absorbed dose of broad and narrow light ion beams in water are investigated. An analytical algorithm based on the generalized Fermi-Eyges theory is developed and used to calculate the effects of multiple scattering and range straggling on the dose distribution of light ion beams in water. A first-order Gaussian multiple scattering and energy loss straggling approach is generally sufficiently accurate for describing the lateral and longitudinal spread of the Bragg peak and the associated energy deposition distribution of therapeutic light ion beams at ranges of clinical interest. Nuclear reactions are not taken into account in this study. The analytical algorithm given in the present study allows an accurate description of the radial spread and the range straggling of light ions traversing matter. A verification of this approach by comparing with experimental data, Monte Carlo methods and other analytical techniques will be presented in a forthcoming paper.

Biologically effective doses in radiotherapy of cervical carcinoma*.

Presented study evaluates biologically effective dose (BED) in patients receiving low-medium dose-rate (LDR/MDR) brachytherapy (BRT) plus external beam radiotherapy (XRT) based on tumor cell proliferation values in cancer of the cervix patients. This study includes 229 patients treated entirely by radiotherapy at the Centre Oncology in Krakow. Doses to Point A were estimated for total treatment for each brachytherapy insertion. BED3 were calculated for reference points in the rectum. The linear quadratic equation was used to calculate BED, which is proportional to log cell kill, and the normalized total dose (NTD), that is, equivalent to a 2 Gy fraction schedule. In BEDs 10 calculation overall treatment time for each patient. Tumor proliferation rate was based on Bromodeoxyuridine labeling index (BrdUrdLI) assessed on biopsy material before beginning the radiotherapy. Total BED at those points was summed for each patient. The medium overall treatment time was 90 days (range 30--210). The mean calculated total BED for point A for tumour and "early reactions" was equal to 104.0 Gy10 and 229.0 Gy3 for the rectum, equivalent to NTD=86.6 Gy and 137.4 Gy in 2 Gy fractions, respectively. Kaplan-Meier analysis revealed that age >50 years, higher than mean BRBEDs and totBEDs doses, gaps in treatments shorter than 40 days and disease free survival (DFS) was significant prognostic factor for overall survival. In the multivariate Cox anaysis age >50 years, BRBED10 >77 Gy and gaps ?40 days appeared to be significant for overall survival. None of the examined parameters was significant for tumor control. However, patients age and shorter gaps in the treatment were predictive for DFS.

Low and high LET radiation-induced apoptosis in M059J and M059K cells.

PURPOSE: To investigate and compare the ability of DNA-dependent protein kinase (DNA-PK)-deficient and -proficient cells to undergo apoptosis after exposure to low and high linear energy transfer (LET) radiation. MATERIALS AND METHODS: A human glioma cell line M059J lacking the catalytic subunit of DNA-PK (DNA-PKcs) and its DNA-PKcs-proficient counterpart, M059K, were exposed to 1 and 4 Gy of accelerated nitrogen ions (14N, 140 eV nm(-1), 8-12 Gy min(-1)) or 60Co gamma-rays (0.2 eV nm(-1), 0.7 Gy min(-1)). The induction of apoptosis was studied up to 144 h post-irradiation using two different methods: morphological characterization of apoptotic cells after fluorescent staining and cell size distribution analysis to detect apoptotic bodies. In parallel, protein expression of DNA-PKcs and poly(ADP-ribose) polymerase (PARP) as well as DNA-PK and caspase-3 activity were investigated. RESULTS: Low and high LET radiations (4 Gy) induced a time-dependent apoptotic response in both cell lines. Low LET radiation induced a significantly elevated apoptotic response in M059J as compared with M059K cells at 144 h post-irradiation. Following high LET radiation exposure, there was no difference between the cell lines at this time. PARP cleavage was detected in M059J cells following both low and high LET irradiation, while only high LET radiation induced PARP cleavage in M059K cells. These cleavages occurred in the absence of caspase-3 activation. CONCLUSIONS: M059J and M059K cells both display radiation-induced apoptosis, which occur independently of caspase-3 activation. The apoptotic course differs between the two cell lines and is dependent on the quality of radiation.

Repairable-conditionally repairable damage model based on dual Poisson processes.

The advent of intensity-modulated radiation therapy makes it increasingly important to model the response accurately when large volumes of normal tissues are irradiated by controlled graded dose distributions aimed at maximizing tumor cure and minimizing normal tissue toxicity. The cell survival model proposed here is very useful and flexible for accurate description of the response of healthy tissues as well as tumors in classical and truly radiobiologically optimized radiation therapy. The repairable-conditionally repairable (RCR) model distinguishes between two different types of damage, namely the potentially repairable, which may also be lethal, i.e. if unrepaired or misrepaired, and the conditionally repairable, which may be repaired or may lead to apoptosis if it has not been repaired correctly. When potentially repairable damage is being repaired, for example by nonhomologous end joining, conditionally repairable damage may require in addition a high-fidelity correction by homologous repair. The induction of both types of damage is assumed to be described by Poisson statistics. The resultant cell survival expression has the unique ability to fit most experimental data well at low doses (the initial hypersensitive range), intermediate doses (on the shoulder of the survival curve), and high doses (on the quasi-exponential region of the survival curve). The complete Poisson expression can be approximated well by a simple bi-exponential cell survival expression, S(D) = e(-aD) + bDe(-cD), where the first term describes the survival of undamaged cells and the last term represents survival after complete repair of sublethal damage. The bi-exponential expression makes it easy to derive D(0), D(q), n and alpha, beta values to facilitate comparison with classical cell survival models.

Relative biological effectiveness of boron ions on human melanoma cells.

PURPOSE: To compare the difference in relative biological effectiveness (RBE) between (10)B ions and a (60)Co gamma-ray beam for human melanoma cells using in vitro cell survival based on a clonogenic assay. MATERIALS AND METHODS: Cells were irradiated in vitro under aerobic conditions with (60)Co and (10)B ions with different linear energy transfer (LET) (40, 80 and 160 eV nm(-1)). The dose to the cells was determined using ferrous sulphate dosimetry and an ionisation chamber. The standard linear-quadratic model and the newly proposed repairable conditionally repairable damage (RCR) model were used to calculate the RBE. RESULTS: The RBE at 10% cell survival for 40, 80 and 160 eV nm(-1) boron ions compared with (60)Co were 1.98 (1.83-2.22), 2.85 (2.64-3.11) and 3.37 (3.17-3.58), respectively, of almost independence of the model used in the calculation. CONCLUSIONS: Different cell survival models may generate different RBE, especially at low doses and high cell survival levels.

Comparison of Monte Carlo calculated electron slowing-down spectra generated by 60Co gamma-rays, electrons, protons and light ions.

When analysing the factors affecting the relative biological effectiveness (RBE) of different radiation qualities, it is essential to consider particularly the low-energy slowing-down electrons (around 100 eV to 1 keV) since they have the potential of inflicting severe damage to the DNA. We present a modified and extended version of the Monte Carlo code PENELOPE that enables scoring of slowing-down spectra. mean local energy imparted spectra and average intra-track nearest-neighbour energy deposition distances of the secondary electrons generated by different radiation qualities, such as electrons, photons, protons and light ions in general. The resulting spectra show that the low-linear energy transfer (LET) beams, 60Co gamma-rays and electrons with initial energies of 0.1 MeV and higher, have as expected approximately the same electron slowing-down fluence per unit dose in the biologically important low-energy interval. Consistent with the general behaviour of the RBE of low-energy electrons, protons and light ions, the low-energy electron slowing-down fluence per unit dose is larger than for low-LET beams, and it increases with decreasing initial projectile energy.

Radiation response of hypoxic and generally heterogeneous tissues.

PURPOSE: Biologically based treatment optimisation can be based on the local mean values of the number of clonogenic cells and the cellular radiation response taken over macroscopic tissue voxels. Steep oxygen gradients in tumours may often lead to microscopic distributions of radiation resistance at the cellular level, far beyond the geometrical resolution of current diagnostic and radiotherapeutic methods. The present work focuses on quantifying the radiobiological effect of such microscopic distributions through tissue-oxygenation modelling and on calculating the corresponding radiation response on both micro- and macroscopic scales. MATERIALS AND METHODS: A simple model of tissue vasculature was developed with microvascular density and heterogeneity as its main parameters. New analytical expressions are presented for calculating the effective radiation response of tissues with generally heterogeneous radiation resistance and clonogen density. RESULTS: The oxygen distributions derived for different parameter sets agree very well with clinically measured oxygen distributions for both tumours and normal tissues. In addition to the vascular density, vascular heterogeneity is an important factor while estimating the hypoxic fraction in tissue. It is shown that both the local and global dose-response relation for tissues with heterogeneous radiation resistance can be accurately calculated from the effective initial clonogen number N(0,eff) and the effective radiation resistance D(0,eff). New equations are derived for calculating these quantities, for instance, from measured oxygen distributions. CONCLUSIONS: With the new methods presented here, existing techniques to measure the micro- and macroscopic oxygen distribution either using standard tumour-type or patient-specific oxygenation data can be used for biologically based treatment plan optimisation.

RBE of 50 MV scanned bremsstrahlung beams determined using clonogenic assay.

PURPOSE: In order to compare the biological effectiveness of a 50 MV scanned bremsstrahlung beam to (60)Co and 6 MV photons, the survival of Chinese hamster cells (V79-379A), human normal fibroblasts cells (GSH(+/+)) and human small cell lung cancer cells (U-1690) were analysed. MATERIALS AND METHODS: Cells were irradiated in vitro under aerobic conditions in a plastic phantom. Dose to the cells was determined using ferrous sulphate and ionization chamber dosimetry. A number of cell survival models were fitted to the experimental data, including the standard LQ model with and without the induced repair. In particular, a new model treating damage and repair separately was used in combination with a new technique for accurate RBE determination. RESULTS: The measured RBE for the three cell lines were 0.988 (0.984-0.992), 0.999 (0.996-1.002) and 1.013 (1.009-1.016) for V79-379A, GSH(+/+) and U-1690 respectively and thus 50 MV scanned beams did not differ more than a fraction of a per cent from conventional therapy beams. CONCLUSIONS: The present study gives RBE consistent with previously calculated RBEs based on photonuclear reaction cross-sections of high-energy photons.

Biologically effective uniform dose (D) for specification, report and comparison of dose response relations and treatment plans.

Developments in radiation therapy planning have improved the information about the three-dimensional dose distribution in the patient. Isodose graphs, dose volume histograms and most recently radiobiological models can be used to evaluate the dose distribution delivered to the irradiated organs and volumes of interest. The concept of a biologically effective uniform dose (D) assumes that any two dose distributions are equivalent if they cause the same probability for tumour control or normal tissue complication. In the present paper the D concept both for tumours and normal tissues is presented, making use of the fact that probabilities averaged over both dose distribution and organ radiosensitivity are more relevant to the clinical outcome than the expected number of surviving clonogens or functional subunits. D can be calculated in complex target volumes or organs at risk either from the 3D dose matrix or from the corresponding dose volume histograms of the dose plan. The value of the D concept is demonstrated by applying it to two treatment plans of a cervix cancer. Comparison is made of the D concept with the effective dose (Deff ) and equivalent uniform dose (EUD) that have been suggested in the past. The value of the concept for complex targets and fractionation schedules is also pointed out.

Individualizing cancer treatment: biological optimization models in treatment planning and delivery.

PURPOSE: During the last 30 years radiation therapy has developed from classical rectangular beams via conformation therapy with largely uniform dose delivery, but irregular field shapes, to fully intensity modulated dose delivery where the total dose distribution in the tumor can be fully controlled in three dimensions. This last step has been developed during the last 15-20 years and has opened up the possibilities for truly optimized radiation therapy. METHODS AND MATERIALS: Today it is not only possible to produce almost any desired dose distribution in the tumor volume. It is also possible to deliver the dose distribution, which has the highest probability to cure the patient without inducing severe complications in normal tissues. To fully exploit the advantages of intensity-modulated radiation therapy, quality of life or radiobiologic objectives have to be used, preferably combined with predictive assay of radiation sensitivity. RESULTS: This article will briefly discuss the biologic objective functions and the associated advantages in the treatment outcome using new approaches such as consideration of stochastic variations in sensitivity and optimization of the angle of incidence and fractionation schedule with intensity-modulated beams. Finally, different possibilities for realizing general three-dimensional intensity-modulated dose delivery will be discussed. CONCLUSIONS: Once accurate genetically and/or cell survival based predictive assays become available, radiation therapy will become an exact science allowing truly individual optimization considering also the panorama of side-effects that the patient is willing to accept.