Escalation and intensification of radiotherapy for stage III non-small cell lung cancer: opportunities for treatment improvement.

In this overview we review and model how radiotherapy tumour control and complication rates vary with dose, fractionation, schedule duration, irradiated volume and use of chemotherapy for stage III non-small cell lung cancer (NSCLC), and use the modelling to study the effectiveness of different NSCLC dose-escalation approaches being developed in the UK. Data have been collated for pneumonitis, lung fibrosis, early and late oesophagitis, cord and cardiac complications, and local progression-free survival at 30 months. Dependences of the various end points on treatment-related factors are catalogued and analysed using the linear-quadratic incomplete repair model to account for dose and fractionation effects, making linear corrections for differences in schedule duration, and loosely characterising volume effects using parallel- and series-type concepts. Tolerance limits are calculated for the different end points and distilled into ranges of prescribed dose likely to be tolerable when delivered in 2.5 and 4 week radiation and 6 week chemoirradiation schedules using conformal techniques. Worthwhile ( approximately 20%) gains in 30 month local progression-free survival should be achievable at safely deliverable levels of dose escalation. The analysis suggests that longer schedules may be more beneficial than shorter ones, but this finding is governed by the relative rates of tumour and oesophageal accelerated proliferation, which are quite imprecisely known. Consequently escalated 2.5, 4 and 6 week schedules are being developed; each should lead to useful improvements in local control but it is not yet known which schedule will be most effective.

Prostate Dose-painting Radiotherapy and Radiobiological Guided Optimisation Enhances the Therapeutic Ratio.

AIMS: To describe the treatment of 11 patients with radiobiologically guided dose-painting radiotherapy and report on toxicity. MATERIALS AND METHODS: Boost volumes were identified with functional magnetic resonance imaging scans in 11 patients with high-risk prostate cancer. Patients were treated using a dose-painting approach; the boost dose was limited to 86 Gy in 37 fractions, while keeping the rectal normal tissue complication probability to 5-6%. Rotational intensity-modulated radiotherapy was used with daily image guidance and fiducial markers. RESULTS: The median dose to the prostate (outside the boost volume) and urethra was 75.4 Gy/37 fractions (range 75.1-75.8 Gy), whereas the median boost dose was 83.4 Gy (range 79.0-87.4 Gy). The tumour control probability (TCP) (Marsden model) increased from 71% for the standard plans to 83.6% [76.6-86.8%] for the dose-painting boost plans. The mean (Lyman-Kutcher-Burman) normal tissue complication probability for rectal bleeding was 5.2% (range 3.3-6.2%) and 5.2% for faecal incontinence (range 3.6-7.8%). All patients tolerated the treatment well, with a low acute toxicity profile. At a median follow-up of 36 months (range 24-50) there was no grade 3 late toxicity. Two patients had grade 2 late urinary toxicity (urethral stricture, urinary frequency and urgency), one patient had grade 1 and one grade 2 late rectal toxicity. The mean prostate-specific antigen at follow-up was 0.81 ng/ml after stopping hormone therapy; one patient relapsed biochemically at 32 months (2.70 ng/ml). CONCLUSIONS: The toxicity for this radiobiological guided dose-painting protocol was low, but we have only treated a small cohort with limited follow-up time. The advantages of this treatment approach should be established in a clinical trial.

Addendum to the IPEMB code of practice for the determination of absorbed dose for x-rays below 300 kV generating potential (0.035 mm Al-4 mm Cu HVL).

This addendum to the code of practice for the determination of absorbed dose for x-rays below 300 kV has recently been approved by the IPEM and introduces three main changes: (i) Due to a lack of available data the original code recommended a value of unity for k(ch) in the very-low-energy range (0.035-1.0 mm Al HVL). A single table of k(ch) values, ranging from 1.01 to 1.07, applicable to both designated chamber types is now presented. (ii) For medium-energy x-rays (0.5-4 mm Cu HVL) methods are given to determine the absorbed dose to water either at 2 cm depth or at the surface of a phantom depending on clinical needs. Determination of the dose at the phantom surface is derived from an in-air measurement and by extending the low-energy range up to 4 mm Cu HVL. Relevant backscatter factors and ratios of mass energy absorption coefficients are given in the addendum. (iii) Relative dosimetry: although not normally forming part of a dosimetry code of practice a brief review of the current literature on this topic has been added as an appendix. This encompasses advice on techniques for measuring depth doses, applicator factors for small field sizes, dose fall off with increasing SSD and choice of appropriate phantom materials and ionization chambers.

Prospects for proton-beam radiotherapy.

Proton beams are already being employed for radiation therapy in 15 centres worldwide and over a dozen more are planned. Good clinical results have been reported in uveal melanomas and in sarcomas of the skull base. Calculated dose distributions for the treatment of brain, lung, head and neck and pelvic tumours predict an improvement relative to multiple-field or conformal photon radiotherapy. Protons may well provide high-precision radiotherapy that will lead to improved treatment of certain tumours in specific anatomical locations.

The delta-TCP concept: a clinically useful measure of tumor control probability.

PURPOSE: The aim of this article is to provide a quantitative tool to evaluate the influence of the different dose regions in a non-uniformly irradiated tumour upon the probability of controlling that tumor. METHODS AND MATERIALS: First, a method to generate a distribution of the probability of controlling the cells in a voxel (VCP) is explored and found not to be useful. Second, we introduce the concept of delta-TCP, which represents the gain or loss in the overall TCP as a result of each particular bin in a DVH not receiving the prescribed dose (the same concept is applicable to dose cubes or to a fraction of the bin). The delta-TCP method presented here is based on the Poisson TCP model, but any other model could also be used. Third, using this tool, with parameters appropriate to Stage C prostate tumors, the consequences of "cold" and "hot" dose regions have been explored. RESULTS: We show that TCP is affected by the minimum dose, even if it is delivered to a very small volume (20% dose deficit to 5% of the volume makes the TCP decrease by 18%), and that a hot region may be "wasted" unless the boost is to the bulk of the volume. An example of the application of the delta-TCP concept to a prostate radiotherapy plan is also given. CONCLUSION: The delta-TCP distribution adds more objective information to the original DVH by enabling the clinician or planner to directly evaluate the effects of a non-uniform dose distribution on local control.

Individualization of dose prescription based on normal-tissue dose-volume and radiosensitivity data.

PURPOSE: The aim of this paper is to illustrate the potential gain in tumor control probability (TCP) of prostate cancer patients by individualizing the prescription dose according to both normal-tissue (N-T) dose-volume and radiosensitivity data. METHODS AND MATERIALS: Two exercises have been carried out. Firstly, patients' dose prescriptions were individualised on the basis of N-T dose-volume histograms (DVHs) alone and secondly modeling potential differences in N-T sensitivity as well. In both cases, the change in tumor control that may be achieved by individualizing patients' dose was estimated assuming that after the dose adjustments, every patient had (1) the same value of normal tissue complication probability (NTCP) (5%) and (2) NTCP equal to the average NTCP before individualization (i.e., without increasing the average NTCP). The Lyman-Kutcher-Burman NTCP model was used to predict the N-T response curves with two different sets of parameters. The first exercise, based only on individual NT DVHs (i.e., assuming all patient equally radiosensitive), was over a real population of 50 prostate cancer patients. The second exercise modeled a 10,000-prostate-cancer patient population with varying NT dose-volume distributions and radiosensitivity (through allowing TD(50) to vary). RESULTS: A gain of more than 9% in TCP was predicted when doses were individualized based only on DVHs so that every patient had 5% NTCP after dose adjustments. By adding the estimate of radiosensitivity, the gain increased to more than 15%. When the individualisation was performed without increasing the mean NTCP, then the potential gain in TCP was almost 5% (for adjustment based on DVH distribution solely) increasing to 7% with the additional consideration of radiosensitivity. CONCLUSIONS: There is a potential gain (increase in local tumor control) from dose individualisation strategies based on both N-T dose-volume data and radiosensitivity (assuming that this is available). Dose prescription individualization based only on dose-volume data can be exploited provided that reliable N-T response models are available. There will be additional gains if some estimate of N-T radiosensitivity is available to allow further patient stratification, identification of patients with high radiosensitivity being particularly important.

Correlations between dose-surface histograms and the incidence of long-term rectal bleeding following conformal or conventional radiotherapy treatment of prostate cancer.

BACKGROUND AND PURPOSE: In a randomized trial, the incidence of rectal bleeding among patients treated for prostate cancer using conformal radiotherapy was significantly lower (p = 0.002) than that among those treated conventionally. Here the relationship between rectal dose distributions and incidences of bleeding is assessed. METHODS AND MATERIALS: Rectal dose-surface histograms (DSHs) have been calculated for 79 trial patients. The relationship between the DSHs and incidences of Grade 1-3 bleeding has been explored using both semiempiric and biologic (parallel) model-based approaches. RESULTS: Semiempiric analysis of the trial data suggests that it is more useful to work with DSH fractional surface areas multiplied by outlined rectal lengths than with either raw DSH fractional areas or fractional areas multiplied by absolute total outlined rectal surface area. Fitting the parallel model to length-multiplied rectal DSHs and complication data reveals the existence of a significant volume effect, the rate of Grade 1-3 bleeding falling by 1.1% (95% confidence interval [0.04, 2.2]%) for each 1% decrease in the fraction of rectal wall (outlined over an 11-cm length) receiving a dose of more than 57 Gy. CONCLUSION: The existence of this volume effect suggests that dose escalation can be achieved using conformal techniques, although the extent to which doses may be safely escalated cannot be reliably estimated from the trial data.

Radiation response and cure rate of human colon adenocarcinoma spheroids of different size: the significance of hypoxia on tumor control modelling.

PURPOSE: To evaluate the adequacy of a Poisson tumor control probability (tcp) model and the impact of hypoxia on tumor cure. METHODS AND MATERIALS: A human colon adenocarcinoma cell line, WiDr, was grown as multicellular spheroids of different diameters. Measurements were made of cell survival and spheroid cure following 300-kV X-ray external beam irradiation in air and nitrogen. Cell survival data were fitted using a two-compartment and an oxygen diffusion model. Spheroid cure data were fitted using the tcp model. RESULTS: Hypoxia was seen only for spheroids greater than 500 microm in diameter. For small spheroids tcp estimates of radiosensitivity and clonogenic number showed excellent agreement with experimentally derived values. For large spheroids, although tcp estimates of radiosensitivity were comparable with measurements, estimates of the clonogenic number were considerably lower than the experimental count. Reoxygenation of large spheroids before irradiation resulted in the tcp estimates of the number of clonogenic cells agreeing with measured values. CONCLUSIONS: When hypoxia was absent, the tcp model accurately predicted cure from measured radiosensitivity and clonogen number. When hypoxia was present, the number of cells capable of regrowth in situ was considerably lower than the number of clonogenic cells that initially survived irradiation. As this counteracted the decreased radiosensitivity, hypoxia was less important for cure than predicted from cell survival assays. This finding suggests that chronic hypoxia may not limit directly the success of radiation therapy.

Incorporating biologic measurements (SF(2), CFE) into a tumor control probability model increases their prognostic significance: a study in cervical carcinoma treated with radiation therapy.

PURPOSE: To assess whether incorporation of measurements of surviving fraction at 2 Gy (SF(2)) and colony-forming efficiency (CFE) into a tumor control probability (tcp) model increases their prognostic significance. METHODS AND MATERIALS: Measurements of SF(2) and CFE were available from a study on carcinoma of the cervix treated with radiation alone. These measurements, as well as tumor volume, dose, and treatment time, were incorporated into a Poisson tcp model (tcp(alpha,rho)). Regression analysis was performed to assess the prognostic power of tcp(alpha,rho) vs. the use of either tcp models with biologic parameters fixed to best-fit estimates (but incorporating individual dose, volume, and treatment time) or the use of SF(2) and CFE measurements alone. RESULTS: In a univariate regression analysis of 44 patients, tcp(alpha,rho) was a better prognostic factor for both local control and survival (p < 0.001 and p = 0.049, respectively) than SF(2) alone (p = 0.009 for local control, p = 0.29 for survival) or CFE alone (p = 0.015 for local control, p = 0.38 for survival). In multivariate analysis, tcp(alpha,rho) emerged as the most important prognostic factor for local control (p < 0.001, relative risk of 2.81). After allowing for tcp(alpha,rho), CFE was still a significant independent prognostic factor for local control, whereas SF(2) was not. The sensitivities of tcp(alpha,rho) and SF(2) as predictive tests for local control were 87% and 65%, respectively. Specificities were 70% and 77%, respectively. CONCLUSIONS: A Poisson tcp model incorporating individual SF(2), CFE, dose, tumor volume, and treatment time was found to be the best independent prognostic factor for local control and survival in cervical carcinoma patients.

Recent developments in basic dosimetry.

CCEMRI(I) (1985) has recommended that from January 1st 1986 the Primary Standard Dosimetry Laboratories (PSDLs) should adopt new values for W/e (33.97 J/C), stopping powers for electrons (ICRU Report 37, 1984), g value in air for 60Co (3.2 X 10-3), and energy absorption coefficients [17]. The consistency of the whole dosimetric chain requires the same basic physical data at the users' beam quality and PSDLs, but most of the existing dosimetry protocols are not generally based on such a set of data and in some cases old and new data have been employed together. A review of the basic data included in the dosimetry protocols is presented here, together with a comparison with experimental data. The most recent data include the recommendations of CCEMRI(I) and at the same time, some of the inconsistencies existing in dosimetry protocol have been eliminated. The new set of data is presented in this work. New dosimetry protocols and updated versions of protocols published before 1986 are discussed in terms of their basic data.

A comparison of techniques for stereotactic radiotherapy by linear accelerator based on 3-dimensional dose distributions.

In order to establish the appropriate beam arrangement for use in stereotactic radiotherapy using a linear accelerator, dose volume distributions were calculated for a number of spherical targets in a head phantom and assessment was made by dose sparing of normal tissue outside the target volume. Using a single isocentre, fixed beam arrangements were compared with single and multiple non-coplanar isocentric arc rotations at target sizes from 10 to 55 mm diameter on a 6 MV Philips linear accelerator. From the dose-volume histograms produced, an arrangement of 3 or 4 arcs of rotation proved most suitable, in terms of sparing of normal tissue outside the target volume to high dose irradiation, across the range of target sizes studied. There was little further benefit with increasing the number of arcs beyond this. At target sizes greater than 20 mm diameter an arrangement of 6 static non-coplanar beams achieved sparing equivalent to multiple arc rotations and may have considerable advantages in the treatment of irregular volumes where customised beam shaping could be employed.

A comparison of proton and megavoltage X-ray treatment planning for prostate cancer.

Conformal photon and proton therapy plans for prostate cancer have been compared in an attempt to quantify the potential advantages of using protons. Two X-ray plans (3-field, 6-field) and a 2-field proton plan were made and compared for each of 20 T3 prostate patients with the aid of the 3D planning system VOXELPLAN. Dose distributions were analysed in terms of dose-volume histograms (DVH). Tumour control probability (TCP) and normal tissue complication probability (NTCP) were computed using our own and the Lyman-Kutcher-Burman models, respectively. The study shows that on average the proton technique results in the best dose distribution, giving the lowest rectal complication probability, and also that the 3-field X-ray technique is more effective than the 6-field X-ray technique in sparing the rectum. At 5% rectal NTCP, the predicted proton average TCP for the 20 patients is 2% (in absolute terms) greater than that obtained using 3-field X-ray therapy. For 7 of the patients the gain in TCP is more than 3%. For the same rectal NTCP as the 3-field X-ray plan with a 64 Gy mean target dose, the use of protons increases the TCP by 2% on average, but for 5 of the patients the increases are greater than 4%. The result is in general positive towards the use of protons but a few patients do not benefit from it and this indicates the importance of patient selection for maximum clinical benefit.

Stereotactic radiotherapy of irregular targets: a comparison between static conformal beams and non-coplanar arcs.

Stereotactic radiotherapy using a linear accelerator is usually equated with the technique of delivery using multiple non-coplanar arcs, which achieves a spherical dose distribution. As the majority of intracranial lesions are not spherical, a range of schematized tumour shapes were planned to assess the role of static conformal beams in the treatment of irregular lesions. A sphere and 2 ellipsoids, ranging from 20 to 50 mm maximum diameter located intracranially were planned using 3, 4, and 6 non-coplanar static beams with conformal blocks and were compared with four 120 degree non-coplanar arcs. Comparison of the plans was made by the relative sparing of normal tissue outside the target volume using three-dimensional dose-volume distributions. Non-coplanar arcs spared more normal tissue at low isodoses and achieved the best high dose sparing for spherical targets. For the majority of irregular targets, 3 and 4 static beams spared more tissue at doses > or = 50% and > or = 80% than the arc technique. For all irregular volumes, maximum sparing of normal tissue to isodoses > or = 50% and > or = 80% of the treatment isodose was obtained with 6 static conformal beams. We conclude that irregularly shaped tumours suitable for stereotactic radiotherapy with a linear accelerator are better treated with conformal static non-coplanar beams rather than with the multiple arc technique.

Conformal radiotherapy of the pelvis: assessment of acute toxicity.

During the last 3 years the Royal Marsden Hospital (RMH) has conducted a prospective randomised trial of conformal pelvic radiotherapy in which dose/volume data and acute toxicity scores have been determined prospectively. Pending completion of the trial, a preliminary analysis has been undertaken of the volume reductions achieved, and of some of the symptom scores. The average symptom score increased during radiotherapy, more markedly for bowel than bladder symptoms. In comparing total doses of 30-38 Gy with 56-65 Gy, watery bowel motions were more frequent with the higher doses (p = 0.013) but in the high-dose group neither this symptom nor tenesmus correlated with volume of rectum treated to at least 90% of the prescribed dose. We conclude that the assessment of the impact of volume on the level of acute symptoms in pelvic radiotherapy is complex, and requires analysis of a range of symptoms, dose levels and normal-tissue volumes. The degree of symptom reduction from conformal radiotherapy will emerge from the RMH randomised trial within the next 12 months.

Acute toxicity in pelvic radiotherapy; a randomised trial of conformal versus conventional treatment.

BACKGROUND: A prospective, randomized clinical trial to assess the effect of reducing the volume of irradiated normal tissue on acute reactions in pelvic radiotherapy accured 266 evaluable patients between 1988 and 1993. PURPOSE: This is the definitive analysis to assess the differences between the conformal and conventional arms of the trial. MATERIALS AND METHODS: In both arms, patients were treated with 6 MV X-rays using a 3-field technique (in all but 5 cases) consisting of an anterior and two wedged lateral or posterior oblique fields; in the conventional arm, rectangular fields were employed, whereas in the conformal arm, the fields were shaped with customized blocks drawn according to the beam's-eye-view of the target volume. The most common dosage was 64 Gy in 2-Gy fractions 5 times a week, although a subgroup (of ca. bladder patients) were treated with 30-36 Gy in once-a-week 6 Gy fractions. Each patients completed a comprehensive acute toxicity scoring questionnaire concentrating on bowel and bladder problems, tiredness and nausea, before the start of treatment, weekly during and for 3 weeks after the end of treatment and then monthly for a further 2 months. compliance was excellent. RESULTS: There were no differences between the patients in the two arms with respect to age, gender, tumour type (52% prostate, 41% bladder, 5% rectum, 2% other) fractionation/dosage, anterior field size, weight, or baseline symptoms. Substantial differences in normal-tissue volumes (rectum, bladder, etc.) were achieved: median high-dose volume (HDV) of 689 cm3 for the conformal technique versus 792 cm3 for the conventional. A clear pattern of an increase in symptoms during RT, followed by a decrease after RT, was observed for the patient group as a whole. However, a very extensive analysis has not revealed any (statistically) significant differences between the two arms in level of symptoms, nor in medication prescribed. The disparity between our findings and those of other, non-randomized studies is discussed. CONCLUSIONS: The data on late effects must be collected and analyzed before any definite conclusions can be drawn on the benefits of conformal therapy in the pelvis.

The Royal Marsden Hospital pelvic radiotherapy trial: technical aspects and quality assurance.

Planning and quality control procedures are described for a randomised trial designed to measure the effect on normal tissue toxicity of reducing the volume of normal tissue irradiated through the introduction of Beams-Eye-View designed customised blocks. Consideration is given to the accuracy with which blocks can be designed and to the potential application of multi-leaf collimator technology.

Impact of dose-distribution uncertainties on rectal ntcp modeling. I: Uncertainty estimates.

A trial of nonescalated conformal versus conventional radiotherapy treatment of prostate cancer has been carried out at the Royal Marsden NHS Trust (RMH) and Institute of Cancer Research (ICR), demonstrating a significant reduction in the rate of rectal bleeding reported for patients treated using the conformal technique. The relationship between planned rectal dose-distributions and incidences of bleeding has been analyzed, showing that the rate of bleeding falls significantly as the extent of the rectal wall receiving a planned dose-level of more than 57 Gy is reduced. Dose-distributions delivered to the rectal wall over the course of radiotherapy treatment inevitably differ from planned distributions, due to sources of uncertainty such as patient setup error, rectal wall movement and variation in the absolute rectal wall surface area. In this paper estimates of the differences between planned and treated rectal dose-distribution parameters are obtained for the RMH/ICR nonescalated conformal technique, working from a distribution of setup errors observed during the RMH/ICR trial, movement data supplied by Lebesque and colleagues derived from repeat CT scans, and estimates of rectal circumference variations extracted from the literature. Setup errors and wall movement are found to cause only limited systematic differences between mean treated and planned rectal dose-distribution parameter values, but introduce considerable uncertainties into the treated values of some dose-distribution parameters: setup errors lead to 22% and 9% relative uncertainties in the highly dosed fraction of the rectal wall and the wall average dose, respectively, with wall movement leading to 21% and 9% relative uncertainties. Estimates obtained from the literature of the uncertainty in the absolute surface area of the distensible rectal wall are of the order of 13%-18%. In a subsequent paper the impact of these uncertainties on analyses of the relationship between incidences of bleeding and planned rectal dose-distributions is explored.

Calculation of absorbed dose ratios using correlated Monte Carlo sampling.

A correlated sampling variance reduction technique has been implemented in the EGS4 (Electron Gamma Shower version 4) Monte Carlo code system in order to calculate correction factors for radiation dosimeters. These correction factors are calculated as the ratios of absorbed doses in various geometries irradiated by photon and electron beams. In this paper the efficiency and accuracy of the calculation of the absorbed dose ratios with correlated Monte Carlo sampling is discussed. Theoretical analysis shows that the calculation efficiency and accuracy increases with the degree of correlation between the calculated doses in the individual geometries. Calculations of the absorbed doses in thin slab geometries and in air-filled ionization chambers have been performed. The results show that the gain in computing efficiency is up to a thousand fold for the calculations of the effect of the central electrode material and size on the response of cylindrical ionization chambers. The calculation accuracy (systematic uncertainty) is significantly improved when good correlation exists between the calculated doses in similar thin-slab geometries.

An analysis of the relationship between radiosensitivity and volume effects in tumor control probability modeling.

The dependence of local tumor control probability (tcp) on tumor volume is analyzed and discussed with the help of radiobiological modeling; in particular the impact of possible correlations between mean tumor radiosensitivity and tumor dimensions on the tcp volume dependence is explored. The linear-quadratic Poissonian tumor control probability (tcp) model was modified to account for the possible dependence of clonogenic cell density and radiosensitivity parameters on tumor volume; then the original and modified versions of the model were fitted to published clinical and laboratory tumor control data. These different versions of the tcp model often fitted tumor control data equally well, because of the high degree of correlation between the parameters. Nevertheless the results were very different from a physical point of view and we suggest that sometimes it is possible to choose between equally good fits on the basis of physical considerations. Possible links between the volume dependence of the mean radiosensitivity and the degree of tumor hypoxia were also analyzed through a comparison of the results of the tcp fit to published measurements of oxygen tension in tumors.

Monte Carlo calculation of output factors for circular, rectangular, and square fields of electron accelerators (6-20 MeV).

Monte Carlo (MC) techniques can be used to build a simulation model of an electron accelerator to calculate output factors for electron fields. This can be useful during commissioning of electron beams from a linac and in clinical practice where irregular fields are also encountered. The Monte Carlo code BEAM/EGS4 was used to model electron beams (6-20 MeV) from a Varian 2100C linear accelerator. After optimization of the Monte Carlo simulation model, agreement within 1% to 2% was obtained between calculated and measured (with a Si diode) lateral and depth dose distributions or within 1 mm in the penumbral regions. Output factors for square, rectangular, and circular fields were measured using two different plane-parallel ion chambers (Markus and NACP) and compared to MC simulations. The agreement was usually within 1% to 2%. This study was not primarily concerned with minimizing the simulation time required to obtain output factors but some considerations with respect to this are presented. It would be particularly useful if the MC model could also be used to calculate output factors for other, similar linacs. To see if this was possible, the primary electron energies in the MC model were retuned to model a recently commissioned similar linac. Good agreement between calculated and measured output factors was obtained for most field sizes for this second accelerator.