Multifraction Treatments Research Articles

Characterizing Proton-Induced Biological Effects in a Mouse Spinal Cord Model: A Comparison of Bragg Peak and Entrance Beam Response in Single and Fractionated Exposures

Proton relative biological effectiveness (RBE) is a dynamic variable influenced by factors like linear energy transfer (LET), dose, tissue type, and biological endpoint. The standard fixed proton RBE of 1.1, currently used in clinical planning, may not accurately represent the true biological effects of proton therapy (PT) in all cases. This uncertainty can contribute to radiation-induced normal tissue toxicity in patients. In late-responding tissues such as the spinal cord, toxicity can cause devastating complications. This study investigated spinal cord tolerance in mice subjected to proton irradiation and characterized the influence of fractionation on proton- induced myelopathy at entrance (ENT) and Bragg peak (BP) positions. Cervical spinal cords of 8-week-old C57BL/6J female mice were irradiated with single- or multi-fractions (18x) using lateral opposed radiation fields at 1 of 2 positions along the Bragg curve: ENT (dose-mean LET = 1.2 keV/μm) and BP (LET = 6.9 keV/μm). Mice were monitored over 1 year for changes in weight, mobility, and general health, with radiation-induced myelopathy as the primary biological endpoint. Calculations of the RBE of the ENT and BP curve (RBEENT/BP) were performed. Single-fraction RBEENT/BP for 50% effect probability (tolerance dose (TD50), grade II paresis, determined using log-logistic model fitting) was 1.10 ± 0.06 (95% CI) and for multifraction treatments it was 1.19 ± 0.05 (95% CI). Higher incidence and faster onset of paralysis were seen in mice treated at the BP compared with ENT. The findings challenge the universally fixed RBE value in PT, indicating up to a 25% mouse spinal cord RBEENT/BP variation for multifraction treatments. These results highlight the importance of considering fractionation in determining RBE for PT. Robust characterization of proton-induced toxicity, aided by in vivo models, is paramount for refining clinical decision-making and mitigating potential patient side effects.

Experimental validation of multi-fraction online adaptations in magnetic resonance guided radiotherapy

Background and purposeRadiotherapy plan verification is generally performed on the reference plan based on the pre-treatment anatomy. However, the introduction of online adaptive treatments demands a new approach, as plans are created daily on different anatomies. The aim of this study was to experimentally validate the accuracy of total doses of multi-fraction plan adaptations in magnetic resonance imaging guided radiotherapy in a phantom study, isolated from the uncertainty of deformable image registration. Materials and methodsWe experimentally verified the total dose, measured on external beam therapy 3 (EBT3) film, using a treatment with five online adapted fractions. Three series of experiments were performed, each focusing on a category of inter-fractional variation; translations, rotations and body modifications. Variations were introduced during each fraction and adapted plans were generated and irradiated. Single fraction doses and total doses over five online adapted fractions were investigated. ResultsThe online adapted measurements and calculations showed a good agreement for single fractions and multi-fraction treatments for the dose profiles, gamma passing rates, dose deviations and distances to agreement. The gamma passing rate using a 2%/2 mm criterion ranged from 99.2% to 99.5% for a threshold dose of 10% of the maximum dose (Dmax) and from 96.2% to 100% for a threshold dose of 90% of Dmax, for the total translations, rotations and body modifications. ConclusionsThe total doses of multi-fraction treatments showed similar accuracies compared to single fraction treatments, indicating an accurate dosimetric outcome of a multi-fraction treatment in adaptive magnetic resonance imaging guided radiotherapy.

GSOR7 Presentation Time: 9:30 AM: Shortening the Learning Curve: Pre-Planning with a Digital Library of 3D Printed Custom Templates for Improved Dosimetry on Day One in Combined Tandem and Ovoid + Interstitial Cases

<h3>Background</h3> In cervical brachytherapy the addition of interstitial (IS) needles to intra-cavitary (IC) applicators can significantly enhance dosimetry by improving target coverage without increasing dose to normal tissues when needles are optimally placed. It usually takes more than one implant to learn and adapt to the patient specific challenges to provide the best possible needle distribution, resulting in improved dosimetry metrics over the course of multi-fraction treatments. <h3>Material and Methods</h3> We developed a digital library of customized supplemental templates that attach to the tandem applicator and guide needles to optimized positions for different tumor topologies. The library consists of CT scans of tandem and ovoid (T&O) applicators with needles guided through these 3D printed templates that can be used for treatment planning (Figure 1A). Following a pre-procedure MRI, CTV contours were drawn and a grid overlaid. Then, an appropriate template can be selected based on tumor dimensions and extent from the uterine canal and a treatment plan generated to best prepare for the first implant (Figure 1B). An appropriate strategy could thus be defined for the first implant, including the specific custom applicator, number of needles and depth of needles. We started using this preplanning library approach in March 2021. We compared the dosimetry of hybrid implants with library preplanning to those that we were not pre-planned from the preceding year and compared the CTV V100%. <h3>Results</h3> Thirteen patients were pre-planned (PP) using the digital library and compared to the previous year's hybrid cases without preplan (n=16). The mean CTV V100% for the no pre-plan (NPP) group was 86.2%, 90.8%, 91.5% and 93.0% for fractions 1-2-3-4 respectively whereas the pre-planning group achieved a V100% of 90.8%, 94.7%, 94.3% and 92.9%. The difference in the first fraction's V100% is statistically significant (p=0.015). Similar dosimetry was achieved in the second fraction of the NPP cohort as compared to the first fraction of the PP cohort, showing the benefit of detailed preplanning (Figure 1C). By taking into account all the available pre-procedure anatomic information and potential implant geometry options in preplanning, many of the challenges of the first applicator insertion can be overcome and thereby shortening the learning curve to optimized dosimetry right from the first implant. <h3>Conclusions</h3> By developing a digital library of customized hybrid applicators and then utilizing it for planning on pre-procedure MRI, we were able to execute dosimetrically on the first fraction what was historically achieved on the second fraction. The pre-planning steps outlined above significantly improved the CTV coverage of the first fraction, showing that many of the patient specific learning steps can be surmounted before the first implant.

Simulated Single Fraction Stereotactic Body Radiation Therapy for the Treatment of Abdominal Oligometastatic Disease with Online Adaptive Magnetic Resonance Guidance: A Feasibility Study

Local ablative therapy improves overall survival in patients with limited oligometastatic disease. Single fraction SBRT is efficient and is safe in several body sites and can provide a high rate of local control, with 20Gy in 1 fraction commonly used in Europe. However, treating metastases in the abdomen is difficult due close proximity to mobile luminal organs and poor visualization on cone beam CT. The purpose of this study is to determine the feasibility of delivering MR-guided adaptive stereotactic body radiation therapy (SBRT) in a single fraction for abdominal metastases. Patients with abdominal metastases within 8mm from luminal organs treated with hypofractionation or SBRT using maximum inhale breath hold (MIBH) respiratory gating on an integrated MR-Linac or MR-cobalt radiotherapy system were retrospectively analyzed. Single fraction SBRT plans were created on the original MRI simulation with dose constraints from the AAPM Task Group 101 and Timmerman et al. Optimized PTVs (PTVopt) created by a Boolean subtraction of the 3-5mm expansion around luminal organs from the 3mm expansion around the GTV. Using a prescription of 24Gy in 1 fraction, goals included PTV V95% > 90%, PTVopt V95% > 90%, and PTVopt D99% > 20Gy with no OAR dose violations. The single fraction plans were tested on 5 fractional MRI scans. Dosimetric data was collected with the original plan (“predicted”) and after the plan was adapted using an isotoxic approach to the daily re-contoured luminal organ anatomy (“Re-optimized”). The Wilcoxon rank sum test was used to compare dosimetric data and the frequency of meeting dosimetric goals between the multi-fraction and single fraction baseline plans and between the predicted and re-optimized fractional plans. Ten patients with abdominal metastases (4 liver, 3 lymph node, 2 kidney, and 1 adrenal site) with GTV mean and range of 25.5 (1.64, 84.2) mL of various histologies were analyzed. The multi-fraction and single fraction plans mean PTV V95% and PTVopt V95% were 89.7% vs. 81.5% and 97.0% vs. 90.9% respectively (all p>0.05), while 2/10 of both the multi-fraction and single fraction plans had a PTVopt V95% < 90%, and no OAR dose constraints were violated. Comparing the predicted and re-optimized fractional plans, there was a statistically significant, 32.8% increase in the mean PTVopt D99% and 68% decrease in the mean frequency of OAR dose violations (Table 1). Single fraction SBRT for the treatment of abdominal metastases with online adaptive MR guidance is feasible and may be an efficient alternative to multi-fraction treatments. Online MR-guided adaptation is required to maintain adequate target coverage while respecting OAR dose constraints.Abstract 2406; TableTable 1: Isotoxic OptimizationMeanFrequencyPTV V95% (%)PTVopt V95% (%)PTVopt D99% (Gy)PTV V95% > 90%PTVopt V95% > 90%PTVopt D99% > 20GyOAR ViolationsPredicted81.187.917.40.240.680.240.68Re-optimized84.892.822.60.420.820.740p-value0.680.310.01*0.160.360.01*0.001* Open table in a new tab

A mathematical model of dynamics of cell populations in squamous epithelium after irradiation

Purpose To develop multi-compartment mechanistic models of dynamics of stem and functional cell populations in epithelium after irradiation. Methods and materials: We present two models, with three (3C) and four (4C) compartments respectively. We use delay differential equations, and include accelerated proliferation, loss of division asymmetry, progressive death of abortive stem cells, and turnover of functional cells. The models are used to fit experimental data on the variations of the number of cells in mice mucosa after irradiation with 13 Gy and 20 Gy. Akaike information criteria (AIC) was used to evaluate the performance of each model. Results Both 3C and 4C models provide good fits to experimental data for 13 Gy. Fits for 20 Gy are slightly poorer and may be affected by larger uncertainties and fluctuations of experimental data. Best fits are obtained by imposing constraints on the fitting parameters, so to have values that are within experimental ranges. There is some degeneration in the fits, as different sets of parameters provide similarly good fits. Conclusions The models provide good fits to experimental data. Mechanistic approaches like this can facilitate the development of mucositis response models to nonstandard schedules/treatment combinations not covered by datasets to which phenomenological models have been fitted. Studying the dynamics of cell populations in multifraction treatments, and finding links with induced toxicity, is the next step of this work.

Utilization of Radiation Fractionation for Bone Metastases at the End of Life in the Era of SBRT: A Large Single Institution Longitudinal Experience

Radiation therapy (RT) is effective in managing painful bone metastases. Multiple randomized trials have demonstrated that single fraction radiotherapy is not inferior to multi-fraction treatments for symptom relief. ASTRO treatment guidelines recommend a single 8Gy fraction to bone metastases for patients with limited life expectancy. We sought to evaluate the use of RT fractionation and the ability of physicians to predict short life expectancy as reflected by their choice of treatment regimen. All patients who received RT for bone metastases (BM) between 2016-2018 at a single institution were identified, as was the subset of patients who died within 30 days after receiving RT for BM. To understand longitudinal trends, treatments were binned into 6-month intervals by date of final radiation treatment. RT fractions were grouped by 8Gy in a single fraction (8Gy x 1), 30Gy in 10 fractions (3Gy x 10), other conventional RT fractionations, and stereotactic body RT (SBRT). To determine the presence of an increasing or decreasing trend, proportions were compared over time using a Chi-square test. The overall change in the use of an RT fractionation was also assessed between the beginning and end of the study period using a 2-sample proportion test. From 2016-2018, 3,056 patients underwent 6,811 palliative RT courses for BM, and 480 patients (16%) died within 30 days of their last treatment. The total number of treatments for BM increased by 27% during the study period. Among all BM treated, use of SBRT had an increasing trend (p<0.001) with a difference in use over the study period (37% to 48%, p<0.001), while 3Gy x10 has a decreasing trend (p<0.001) with a change in use (25% to 11%, p <0.001) and 8Gy x1 has remained stable over time (p=0.4) with no significant difference in use (4.5% to 4.8%, p= 0.8). The trends were mirrored among patients dying within 30 days of RT; SBRT with an increasing trend (p=0.039) and change in use (18% to 33% p= 0.03), 3Gy x10 with a decreasing trend (p<0.001) and change in use (32% to 7%, p<0.001), while the number of patients treated with 8Gyx1 remained stable (p=0.4) with no significant difference in use (9% to 17%, p= 0.2). A 33% relative reduction (9.5% to 6.6%) in death within 30 days of RT was observed. Our study demonstrates an increase in patients undergoing RT for BM over time while the overall rate of death within 30 days of RT has decreased, most likely due to more patients getting treated earlier in their disease course. Of the patients dying within 30 days of RT for bone metastases, a significant decline in the use of 3Gy x10 was observed during the study period, but the use of 8Gy x1 did not increase, potentially related to the increase in use of SBRT. Our results warrant further investigation into algorithms predicting short life expectancy and implementation strategies to increase use 8Gy x1 at the end of life.

Improving radiotherapy quality of care: Examining practice patterns in regional centers.

53 Background: Radiotherapy (RT) is a resource intensive cancer treatment. Benefits may take weeks to realize, whereas side effects are more immediate. RT is commonly delivered with palliative intent often near the end of life (EOL). In patients with limited life expectancy, single fractions (sf) may substitute for multi-fraction (mf) treatments. Objectives were to document RT courses delivered to patients with cancer at EOL, with the goal of informing treatment practices, developing a clinical decision-making tool and reducing potentially futile treatment and side effects for patients. Methods: Cancer Registry data was examined with ethics approval. Patient and prospective treatment data were collected and analyzed to determine the number of RT courses starting within 90 days of death (EOL) among those with cancer diagnoses who died between January 1, 2016, and July 31, 2017. Data was stratified by demographics, disease factors, RT center and prescription factors. Results are reported in aggregate and explored using tests of association (Stata 11.1). Results: Among 1874 patients who died, 2448 RT courses were identified across 4 RT centers. Of those prescribed RT at the EOL, there were 442 sf courses 100% completed, 1267 2-5 fraction courses 90% completed, 552 6-10 fraction courses 77% completed, and 187 11+ fraction courses 57% completed. Among patients prescribed RT 14 days prior to death, 24% had been prescribed a sf of RT compared to 18% of those within 90 days of death (Chi2 17.92, p &lt; 0.001). Among patients prescribed RT 90 days prior to death, 25% of patients in tertiary Centre A were prescribed a sf compared to 13% of patients in tertiary Centre B (Chi2 121.90, p &lt; 0.001). Patients were half as likely (RR = 0.47, 95% CI [0.39, 0.56], p &lt; 0.001) to complete a mf treatment within 14 days of their death as compared to within 90 days. Patients who had a diagnosis to death interval of under a year were less likely to complete RT than those over a year (RR = 0.82, 95% CI [0.79, 0.85], p &lt; 0.001). Conclusions: Multi-fraction RT is often not completed prior to death. Treating RT center is associated with differences in prescribing patterns. Better understanding of factors influencing RT practice patterns may lessen the proportion of potentially futile RT.

A new methodology for inter- and intrafraction plan adaptation for the MR-linac

The new era of hybrid MRI and linear accelerator machines, including the MR-linac currently being installed in the University Medical Center Utrecht (Utrecht, The Netherlands), will be able to provide the actual anatomy and real-time anatomy changes of the patient’s target(s) and organ(s) at risk (OARs) during radiation delivery. In order to be able to take advantage of this input, a new generation of treatment planning systems is needed, that will allow plan adaptation to the latest anatomy state in an online regime. In this paper, we present a treatment planning algorithm for intensity-modulated radiotherapy (IMRT), which is able to compensate for patient anatomy changes. The system consists of an iterative sequencing loop open to anatomy updates and an inter- and intrafraction adaptation scheme that enables convergence to the ideal dose distribution without the need of a final segment weight optimization (SWO). The ability of the system to take into account organ motion and adapt the plan to the latest anatomy state is illustrated using artificial baseline shifts created for three different kidney cases. Firstly, for two kidney cases of different target volumes, we show that the system can account for intrafraction motion, delivering the intended dose to the target with minimal dose deposition to the surroundings compared to conventional plans. Secondly, for a third kidney case we show that our algorithm combined with the interfraction scheme can be used to deliver the prescribed dose while adapting to the changing anatomy during multi-fraction treatments without performing a final SWO.

Fractionated changes in prostate cancer radiotherapy using cone-beam computed tomography

The high mobility of the bladder and the rectum causes uncertainty in radiation doses prescribed to patients with prostate cancer who undergo radiotherapy (RT) multifraction treatments. The purpose of this study was to estimate the dose received by the bladder, rectum, and prostate from multifraction treatments using daily cone-beam computed tomography (CBCT). Overall, 28 patients with prostate cancer who planned to receive radiation treatments were enrolled in the study. The acquired CBCT before the treatment delivery was registered with the planning CT to map the dose distribution used in the treatment plan for estimating the received dose during clinical treatment. For all 28 patients with 112 data sets, the mean percentage differences (± standard deviation) in the volume and radiation dose were 44% (± 41) and 18% (± 17) for the bladder, 20% (± 21) and 2% (± 2) for the prostate, and 36% (± 29) and 22% (± 15) for the rectum, respectively. Substantial differences between the volumes and radiation dose and those specified in treatment plans were observed. Besides the use of image-guided RT to improve patient setup accuracy, further consideration of large changes in bladder and rectum volumes is strongly suggested when using external beam radiation for prostate cancer.

Significant dose can be lost by extended delivery times in IMRT with x rays but not high-LET radiations

To experimentally simulate IMRT delivery using two human cell models in vitro and test the hypothesis that a loss in effective dose resulting from the prolongation of megavoltage x-ray treatment delivery time would be greatly reduced in corresponding IMRT simulations using higher-LET radiation. The effect of prolonging the delivery time of a treatment fraction was investigated in vitro using human PC-3 prostate and HGL21 glioblastoma tumor cell lines. Cells were irradiated with x rays from a conventional linear accelerator or with neutrons from a clinical d(48.5)+Be radiotherapy beam and maintained at 37 degrees C throughout. The delivery time for six closely spaced doses, simulating six multiple-port segments, was varied from acute to 60 min for x-ray irradiation, and acute to 120 min for neutron irradiation. Cell survival was measured following summed doses for the six segments of 0.5-6 Gy for x rays and 0.16-2 Gy for neutrons, covering the most likely range of dose per fraction used in clinical radiotherapy. Prolonging x-ray delivery time (from initiation of segment 1 to initiation of segment 6) from 5 to 45 min resulted in a loss in effective total dose (in equivalent 2 Gy multifraction treatments) of 5.6% in the PC-3 cell line and 11.7% in the HGL21 cell line. More clinically common prolongations of 5-30 and 5-15 min resulted in effective dose reductions of 3.8% and 1.7% for PC-3, and 7.3% and 2.9% for HGL21. A loss of less than 0.5% in effective dose was observed for prolongations up to 45 min of similarly effective neutron irradiation of PC-3 and HGL21 cells. Prolonged delivery times of photon fractions could have a significant impact on treatment outcome especially for tumors with a low alpha/beta ratio and short repair halftime. These effects are significant at delivery times commonly associated with IMRT and are variable with cell type. X-ray IMRT should therefore always be planned to minimize dose-fraction delivery time. However, if IMRT treatments are delivered with high-LET radiation, this considerably reduces the dependence of the biological effect on fraction delivery time even out to 2 h.

External beam radiotherapy for palliation of painful bone metastases: pooled data bioeffect dose response analysis of dose fractionation

External beam radiotherapy for palliation of painful bone metastases: pooled data bioeffect dose response analysis of dose fractionation Bone metastases develop in up to 70% of newly diagnosed cancer patients and result in immobility, anxiety, and depression, severely diminishing the patients quality of life. Radiotherapy is a frequently used modality for bone metastasis and has been shown to be effective in reducing metastatic bone pain and in some instances, causing tumor shrinkage or growth inhibition. There is controversy surrounding the optimal fractionation schedule and total dose of external beam radiotherapy, despite many randomized trials and overviews addressing the issue. This study was undertaken to apply BED to clinical fractionation data of radiotherapeutic management of bone metastases in order to arrive at optimum BED values for acceptable level of response rate. A computerised literature search was conducted to identify all prospective clinical studies that addressed the issue of fractionation for the treatment of bone metastasis. The results of these studies were pooled together to form the database for the analysis. A total of 4111 number of patients received radiation dose ranging from 4 to 40.5 Gy in 1 to 15 fractions with dose per fraction ranging from 2 to 10 Gy. Single fraction treatments were delivered in 2013 patients and the dose varied from 4 to 10 Gy. Multifraction treatments were delivered in 2098 patients and the dose varied from 15 to 40.5 Gy. The biological effective dose (BED) was evaluated for each fractionation schedule using the linear quadratic model and an α/β value of 10 Gy. Response rate increased significantly beyond a BED value of 14.4 Gy (p &lt; 0.01). Based on our analysis and indications from the literature about higher retreatment and fracture rate of single fraction treatments, minimum BED value of 14.4 Gy is recommended.

Cell Kinetics and Repopulation During Multifraction Irradiation of Spheroids: Implications for Clinical Radiotherapy.

T here seems to be little question that development of a predictive assay that could reliably forecast the response of individual tumors to treatment would be of tremendous value to practicing oncologists. However, exactly what type of information is needed in such an assay is less certain. For example, is the determinant of success the inherent sensitivity of the majority, or that of a minority of the tumor cells? Because treatment "failure" is typically recognized by the regrowth or continued growth of the tumor mass, what is the role of cell kinetics in that process? Perhaps of most pressing importance, can predictive assays lead to alternate, hopefully superior, forms of treatment? While measuring tumor cell sensitivity to both radiation and drugs has become fashionable in recent years, correlations between in vitro sensitivity analyses and eventual patient outcome have generally been found only between tumor types, but not between individual tumors of a certain type. This suggests that factors in addition to inherent sensitivity must be considered. Analyzing patterns of failure can often be useful in this regard; in a provocative article analyzing outcomes for patients with head and neck cancer, Withers et al I reached the rather alarming conclusion that treatments lasting more than 4 weeks required a dose escalation of 0.6 Gy/extension day to retain the same probability of cure. More general reviews 2-4 similarly argue for a dose increase of 0.3 to 0.7 Gy/day of treatment for treatment extensions beyond 4 weeks. These results strongly' implicate time as a critical factor for successful treatments. However, identifying a clinical problem is considerably easier than resoMng it. For example, does the repopulation seen at later times during therapy indicate that cells are cycling more rapidly, that more cells are in cycle, that fewer clonogenic cells are "lost," or combinations of the above? When does repopulation actually"accelerate"? Perhaps of greater immediate importance, can reliable and unambiguous methods of measurement be developed for tumor cell kinetics, and when should they be used? Alternatively, can repopulation rate or potential be predicted? Clearly', several philosophical and practical limitations combine to inhibit addressing these questions in the most relevant system, the human cancer patient. At least one tumor model system is available, however, in which many relevant and highly detailed studies can be pursued: the multicell spheroid model. 5,6 It is of particular note that the spheroid system can be easily maintained in long-term culture, allowing large numbers of virtually identical "tumors" to be propagated and reproducibly tested, without host factors complicating the response. 7,8 Every cell of the system potentially contributes to the net response, and of particular importance, each cell can be recovered and assessed. The intent of this article is to examine the role of cell kinetics when spheroids are treated with multifraction protocols. In addition to multifraction radiation treatments, multiple drug exposures will be briefly explored. From the design of these studies, we have been able to address not only the role of pretreatment cell kinetics, but also factors controlling changes of those kinetic properties during, and in response to, the therapeutic manipulations.

A stochastic convolution/superposition method with isocenter sampling to evaluate intrafraction motion effects in IMRT

Current methods to calculate dose distributions with organ motion can be broadly classified as "dose convolution" and "fluence convolution" methods. In the former, a static dose distribution is convolved with the probability distribution function (PDF) that characterizes the motion. However, artifacts are produced near the surface and around inhomogeneities because the method assumes shift invariance. Fluence convolution avoids these artifacts by convolving the PDF with the incident fluence instead of the patient dose. In this paper we present an alternative method that improves the accuracy, generality as well as the speed of dose calculation with organ motion. The algorithm starts by sampling an isocenter point from a parametrically defined space curve corresponding to the patient-specific motion trajectory. Then a photon is sampled in the linac head and propagated through the three-dimensional (3-D) collimator structure corresponding to a particular MLC segment chosen randomly from the planned IMRT leaf sequence. The photon is then made to interact at a point in the CT-based simulation phantom. Randomly sampled monoenergetic kernel rays issued from this point are then made to deposit energy in the voxels. Our method explicitly accounts for MLC-specific effects (spectral hardening, tongue-and-groove, head scatter) as well as changes in SSD with isocentric displacement, assuming that the body moves rigidly with the isocenter. Since the positions are randomly sampled from a continuum, there is no motion discretization, and the computation takes no more time than a static calculation. To validate our method, we obtained ten separate film measurements of an IMRT plan delivered on a phantom moving sinusoidally, with each fraction starting with a random phase. For 2 cm motion amplitude, we found that a ten-fraction average of the film measurements gave an agreement with the calculated infinite fraction average to within 2 mm in the isodose curves. The results also corroborate the existing notion that the interfraction dose variability due to the interplay between the MLC motion and breathing motion averages out over typical multifraction treatments. Simulation with motion waveforms more representative of real breathing indicate that the motion can produce penumbral spreading asymmetric about the static dose distributions. Such calculations can help a clinician decide to use, for example, a larger margin in the superior direction than in the inferior direction. In the paper we demonstrate that a 15 min run on a single CPU can readily illustrate the effect of a patient-specific breathing waveform, and can guide the physician in making informed decisions about margin expansion and dose escalation.

Schedule Dependence for Cisplatin and Etoposide Multifraction Treatments of Spheroids

Cisplatin and etoposide are both widely used as antineoplastic chemotherapeutic agents. Two approaches are generally adopted when an attempt is made to maximize the efficiency of these drugs: concurrent use (where synergism is expected) or sequential administrations (exploiting the antiproliferative effects of etoposide). To differentiate between these approaches in a quantitative manner, we exposed an in vitro tumor model (V79 multicell spheroids) to the drugs, using treatment regimens with a constant weekly dose intensity. Some treatment schedules suggested the development of drug resistance, but this resulted from a changing growth fraction in the spheroids rather than from selection for or induction of cellular resistance. Fewer administrations of larger doses were generally less satisfactory than multiple, smaller treatments. The most effective sequence was an alternating regimen, by which the cytoreductive effects of cisplatin resulted in recruitment of quiescent cells into active proliferation, enhancing in turn the efficiency of subsequent etoposide treatment.

Small-field stereotactic external-beam radiation therapy of intracranial lesions: fractionated treatment with a fixed-halo immobilization device.

Current techniques of stereotactic, small-field, external-beam irradiation with linear accelerators require treatment with a single fraction or only a few fractions of radiation with large single doses per fraction. Using a radiolucent halo that remained affixed to the cranium with skin-piercing screws, the authors treated 24 patients with a multifraction technique for benign and malignant brain lesions. The objective of this study was to ascertain the feasibility of maintaining the halo in place for a prolonged, multifraction course of treatment, not to assess treatment efficacy. The halo was affixed for multifraction treatments lasting 19-58 days (mean, 38.7 days; median, 40.0 days) and delivered in 16-31 fractions (mean, 24.9 fractions; median, 25.5 fractions). Two of 24 patients experienced superficial skin infection at the site of fixation, but no other significant acute or chronic toxicity attributable to the stereotactic halo was observed. The authors conclude that stereotactic, small-field, precision irradiation can be accomplished with multiple fractions as well as with a single fraction.

Changes in the proliferation rate of mouse epidermis after irradiat-on continuous labelling studies.

The proliferative response of mouse skin to damage caused by X-irradiation has been tested by giving repeated injections of tritiated thymidine and scoring the percentage of labelled cells in high resolution autoradiography. Four, nine and fourteen daily fractions of 300 rads of X-rays were used and labelling commenced 4 days after the last fraction. The epidermis of the upper surface and the sole of the foot were scored separately and were compared with the skin of unirradiated feet. In unirradiated skin the proliferation rate of the basal layer cells is more rapid on the sole than on the upper surface. The cell cycle times deduced from continuous labelling curves were 81 hr and 111 hr respectively and the growth fractions were 97% and85%. After irradiation with small daily doses the homeostatic response to cell killing was slow. More rapid proliferation occurred after nine fractions in the sole, but was not apparent in the skin of the upper surface until fourteen fractions had been given. After fourteen fractions the cell cycle time was about 24 hr on both surfaces and the growth fraction was about 90%. The initial labelling index after a single thymidine injection was a poor measure of proliferation rate. The delay in the time of onset of faster proliferation is similar, both qualitatively and quantitatively, to that measured previously from the additional dose increments needed if large doses were given at different times after the multifraction treatments (Denekamp, 1973).