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PURPOSE: An anthropomorphic pelvic phantom was designed and constructed to meet specific criteria for multicenter radiotherapy dosimetric intercomparison. METHODS: Three dimensional external and organ outlines were generated from a computed tomography image set of a male pelvis, forming the basis of design for an anatomically realistic phantom. Clinically relevant points of interest were selected throughout the dataset where point-dose values could be measured with thermoluminescence dosimeters and a small-volume ionization chamber. Following testing, three materials were selected and the phantom was manufactured using modern prototyping techniques into five separate coronal slices. Time lines and resource requirements for the phantom design and manufacture were recorded. The ability of the phantom to mimic the entire treatment chain was tested. RESULTS: The phantom CT images indicated that organ densities and geometries were comparable to those of the original patient. The phantom proved simple to load for dosimetry and rapid to assemble. Due to heat release during manufacture, small air gaps and density heterogeneities were present throughout the phantom. The overall cost for production of the prototype phantom was comparable to other commercial anthropomorphic phantoms. The phantom was shown to be suitable for use as a "patient" to mimic the entire treatment chain for typical external beam radiotherapy for prostate and rectal cancer. CONCLUSIONS: The phantom constructed for the present study incorporates all characteristics necessary for accurate Level III intercomparison studies. Following use in an extensive Level III dosimetric comparison over a large time scale and geographic area, the phantom retained mechanical stability and did not show signs of radiation-induced degradation.

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PURPOSE: To assess dose delivery accuracy to clinically significant points in a realistic patient geometry for two separate pelvic radiotherapy scenarios. METHODS: An inhomogeneous pelvic phantom was transported to 36 radiotherapy centers in Australia and New Zealand. The phantom was treated according to Phase III rectal and prostate trial protocols. Point dose measurements were made with thermoluminescent dosimeters (TLDs) and an ionisation chamber. Comprehensive site-demographic, treatment planning, and physical data were collected for correlation with measurement outcomes. RESULTS: Dose delivery to the prescription point for the rectal treatment was consistent with planned dose (mean difference between planned and measured dose - 0.1 ± 0.3% std err). Dose delivery in the region of the sacral hollow was consistently higher than planned (+1.2 ± 0.2%). For the prostate treatment, dose delivery to the prostate volume was consistent with planned doses (-0.49 ± 0.2%) and planned dose uniformity, though with a tendency to underdose the PTV at the prostate-rectal border. Measured out-of-field doses were significantly higher than planned. CONCLUSIONS: A phantom based on realistic anatomy and heterogeneity can be used to comprehensively assess the influence of multiple aspects of the radiotherapy treatment process on dose delivery. The ability to verify dose delivery for two trials with a single phantom was advantageous.

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The aim of this article was to quantify improvements in external beam treatment plans for early prostate cancer, going from standard four-field conformal radiotherapy (CRT4) to multi-segment, inverse-planned intensity-modulated radiotherapy (IMRTinv). We selected 18 low-, medium- and high-risk early prostate cancer patients requiring external beam radiotherapy and generated standard CRT4 plans. We compared this with five-field conformal radiotherapy (CRT5) plans with beam angles 45 degrees, 100 degrees, 180 degrees, 260 degrees and 315 degrees, five-field plans combining an open beam and rectal shielding segment (forward-planned IMRT (IMRT(for))) and a five-field inverse-planned multi-segment solution (IMRT(inv)) with planning target volume and bladder dose volume histogram characteristics similar to IMRT(for). The CRT5 plans showed significant rectal sparing compared with CRT4 producing 10-22% reductions in rectal volume receiving 95, 85, 67 and 55% prescription dose (V(95), V(85), V(67) and V(55)) depending on patient risk group and conforming better to the planning target volume. The IMRT(for) plans showed a concave dose distribution, further reducing rectal V(95), V(85), V(67) and V(55) between 6 and 50%. We did not find further reductions in rectal doses with IMRT(inv) compared with IMRT(for). The benefit of IMRT over CRT was achieved by increasing the number of beams, changing beam weights and adding a rectal shielding segment to each beam.

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The present paper describes the logistics of the 2004-2008 Australasian Level III Dosimetry Intercomparison. Dosimetric intercomparisons (or 'audits') can be used in radiotherapy to evaluate the accuracy and quality of radiation delivery. An intercomparison was undertaken in New Zealand and Australia to evaluate the feasibility and logistics of ongoing dosimetric intercomparisons that evaluate all steps in the radiotherapy treatment process, known as a 'Level III' intercomparison. The study commenced in 2002 with the establishment of a study team, definition of the study protocol, acquisition of appropriate equipment and recruitment of participating radiotherapy centres. Measurements were undertaken between October 2004 and March 2008, and included collation of data on time, costs and logistics of the study. Forty independent Australian and New Zealand radiotherapy centres agreed to participate. Measurement visits were made to 37 of these centres. Data is presented on the costs of the study and the level of support required. The study involved the participation of 16 staff at the study centre who invested over 4000 hours in the study, and of over 200 professionals at participating centres. Recommendations are provided for future phantom-based intercomparisons. It is hoped that the present paper will be of benefit to any centres or groups contemplating similar activities by identifying the processes involved in establishing the study, the potential hazards and pitfalls, and expected resource requirements.

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Patient set-up in external beam radiotherapy to the thorax is routinely checked by matching anterior and lateral ports to simulator or digitally reconstructed radiograph (DRR) reference images. We report a method to derive bed shifts from matching multiple oblique treatment ports, exploiting data redundancy for match consistency checking. Portal images were acquired for 14 thorax patients on the first 3 treatment days and matched to DRRs. As per clinical practice, anterior and lateral portal images were matched and checked. In addition, treatment ports were acquired and matched and field placement errors calculated from equations generating lateral and ventrodorsal bed shifts from any pair of treatment fields. We compared bed moves obtained from clinical imaging and from oblique treatment fields. Inconsistencies larger than 3 mm triggered a further independent check using new reference anatomy. With clinical image matching, set-up errors had a 95% confidence interval of +/-8 mm ventrodorsal and +/-6 mm in the lateral direction. With independent oblique field re-evaluation, the confidence intervals were reduced to +/-3 mm and +/-2 mm, respectively. Matching using the oblique fields detected set-up errors greater than 5 mm in 16 out of 90 matches. In the clinical environment, match errors greater than 5 mm in the thorax area can remain undetected using anterior and lateral fields only. Consequently, necessary bed shifts are not made or made in error. We developed a technique that uses portal images from multiple oblique treatment fields and exploits data redundancy for internal match consistency checking.

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This paper describes the process and results of a survey of linear accelerator outputs as part of an Australasian Level III Dosimetry Intercomparison. This study involved the measurement of accelerator output under reference conditions ('Level I') with a small-volume ionisation chamber in water for 47 beams at 36 radiotherapy centres using the IAEA TRS 398 dose-to-water protocol. The mean ratio of measured to locally-determined accelerator output was 1.003 +/- 0.009 (1 standard deviation) with a range from 0.981 to 1.024. No correlation could be found between output ratio and accelerator type or local output calibration protocol. The small-volume chamber used satisfied most requirements for the study though showed some variation in sensitivity via repeated cross-calibration with a chamber calibrated at a primary standards laboratory.

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The technologies available to identify anatomical structures (including radiotherapy target and normal tissue 'volumes'), and to deliver dose accurately to these volumes, have improved significantly in the past decade. However, the ability of clinicians to identify volumes accurately and consistently in patients still suffers from uncertainties that arise from human error, inadequate training, lack of consensus on the derivation of volumes and inadequate characterisation of the accuracy and specificity of imaging technologies. Inadequate volume definition of a target can result in treatment failure and, consequently, disease progression; excessive volume may also lead to unnecessary patient injury. This is a serious problem in routine clinical care. In the context of large multi-centre clinical trials, uncertainty and inconsistency in tissue-volume reporting will be carried through to the analysis of treatment effect on outcome, which will subsequently influence the treatment of future patients. Strategies need to be set in place to ensure that the abilities and consistency of clinicians in defining volumes are aligned with the ability of new technologies to present volumetric information. This review seeks to define the concept of volumetric uncertainty and propose a conceptual model that has these errors evaluated and responded to separately. Specifically, we will explore the major causes, consequences of, and possible remediation of volumetric uncertainty, from the point of view of a multidisciplinary radiotherapy clinical environment.

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6-alpha-methylpenicillin N was synthesised via known routes from 6-aminopenicillanic acid, and tested as a substrate for recombinant DAOCS and DAOC/DACS. Incubation with DAOCS resulted in conversion of 2-oxoglutarate without oxidation of the penicillin substrate ('uncoupled turnover'). Incubation with DAOC/DACS resulted in oxidation to the cephem aldehyde. This is the first example of substrate-induced 'uncoupled turnover', which has been proposed to be an editing mechanism for these enzymes.

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Cutaneous oedema is a relatively frequent complication in patients treated conservatively for breast cancer. The factors that contribute to this complication have not been precisely determined. We performed a pilot study to assess the usefulness of high-frequency ultrasound as a quantitative measure of cutaneous oedema. Eleven patients undergoing breast-conserving therapy for breast cancer were studied. Both the treated and untreated breasts were examined. Total cutaneous thickness provided a useful measure of cutaneous oedema. The treated breast was significantly thicker than the untreated breast (P < 0.001). The medial aspect of the breast was thicker than the lateral aspect in both the treated and untreated breast (P < 0.001). The increase in cutaneous thickness predated radiotherapy in those patients who had undergone an axillary dissection. Intrapatient variation in skin thickness was much less than interpatient variation in skin thickness (coefficient of variation 6.4% vs. 18.2% for the untreated breast; coefficient of variation 13.9% vs. 30.9% for the treated breast). Increasing cutaneous thickness was associated with decreasing cutaneous echodensity. We were unable to derive quantitative estimates of echodensity. Cutaneous oedema is an important outcome variable following conservative treatment of breast cancer. High-frequency ultrasound is able to quantify this accurately. It can readily detect changes invisible to the naked eye. High-frequency ultrasound should enable the effects of different treatment options (e.g., extent of surgery, radiotherapy, and chemotherapy) on cutaneous oedema to be differentiated and for the time course of oedema to be accurately characterised.

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On the basis of sequence alignments, the pseudouridine synthases were grouped into four families that share no statistically significant global sequence similarity, though some common sequence motifs were discovered [Koonin, E. V. (1996) Nucleic Acids. Res. 24, 2411-2415; Gustafsson, C., Reid, R., Greene, P. J., and Santi, D. V. (1996) Nucleic Acids Res. 24, 3756-3762]. We have investigated the functional significance of these alignments by substituting the nearly invariant lysine and proline residues in Motif I of RluA and TruB, pseudouridine synthases belonging to different families. Contrary to our expectations, the altered enzymes display only very mild kinetic impairment. Substitution of the aligned lysine and proline residues does, however, reduce structural stability, consistent with a temperature sensitive phenotype that results from substitution of the cognate proline residue in Cbf5p, a yeast homologue of TruB [Zerbarjadian, Y., King, T., Fournier, M. J., Clarke, L., and Carbon, J. (1999) Mol. Cell. Biol. 19, 7461-7472]. Together, our data support a functional role for Motif I, as predicted by sequence alignments, though the effect of substituting the highly conserved residues was milder than we anticipated. By extrapolation, our findings also support the assignment of pseudouridine synthase function to certain physiologically important eukaryotic proteins that contain Motif I, including the human protein dyskerin, alteration of which leads to the disease dyskeratosis congenita.

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PURPOSE: To investigate the significance of the various late rectal symptoms that appear after radical prostatic irradiation. PATIENTS AND METHODS: Patients with localised prostate cancer treated between 1987 and 1994 at the Mater Hospital, Newcastle with radical megavoltage irradiation were recalled for examination and to complete a detailed questionnaire concerning late radiation-induced symptoms and their effects on normal daily life. The influence of patient age treatment related variables and acute proctitis symptoms occurring during therapy or the late symptoms recorded were assessed and the relationship between late symptoms and late EORTC/RTOG score and impact on normal daily life were studied. RESULTS: The presence of symptoms of acute proctitis was the only factor to predict any of three late symptoms (urgency, frequency and diarrhoea) and late EORTC/RTOG score in this series (odds ratios: 1.7-2.57, P-values: 0.009-0.0007). Cluster and discriminant function analyses revealed the presence of five subgroups of patients with varying permutations of different late rectal symptoms, including one group with minimal symptoms (P < 0.0001). While bleeding and rectal discharge were the major contributors to late EORTC/RTOG score (P < 0.0001 and 0.04), faecal urgency and bleeding were the most important factors to impact on normal daily life (P < 0.0001 and P < 0.0003). A relatively low concordance was found between late EORTC/RTOG score and the patients' self assessment on the effect of their symptoms on their normal daily lives. Some late symptoms, including bleeding and rectal discharge become less prevalent after 3 years of follow-up with a resulting improvement in EORTC/RTOG score. CONCLUSIONS: There may be more than one late (chronic) proctitis syndrome which may be linked in greater or lesser degrees to acute proctitis symptoms occurring during therapy. Urgency is a common late symptom which often has an important impact on normal daily life and deserves recognition in late normal tissue scoring systems. Assessment of the incidence of bleeding as a measure of late rectal morbidity following prostate irradiation may underestimate the impact of these chronic effects. Confirmatory studies are necessary.

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Hair cortical cell counting (HCCC) represents a non-invasive, in-vivo measure of cell kill in the human integument. Sixty-six patients undergoing conventionally fractionated, external beam radiotherapy for early stage carcinoma of the prostate had groin hair samples counted. This technique is a sensitive and reproducible measure of radiation effect and may have applicability as an in-vivo prediction tool or in the field of biological dosimetry. A repopulative follicular response occurring at 3-4 weeks may explain flattening of the dose response curve.

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BACKGROUND AND PURPOSE: Regeneration of the aerodigestive mucosa is known to occur during conventionally fractionated radiotherapy. The circumstances surrounding its time of onset and magnitude are not well understood, however. MATERIAL AND METHODS: Mucosal reactions were observed in 100 patients undergoing conventionally fractionated treatment at 2 Gy/day over 7 weeks and 88 receiving accelerated treatment at 1.8 Gy twice daily over 3 1/2 weeks on the Trans Tasman Radiation Oncology Group head and neck cancer trials. Similar observations in 61 patients treated palliatively at dose rates between 0.8 and 240 Gy/h using ten 3.0-4.2 Gy fractions over 2 weeks are compared. RESULTS: Several findings emerged from these studies: 1. Reactions evolved more quickly at oropharyngeal sites than in the hypopharynx. 2. Reactions at both sites evolved more rapidly at greater rates of dose accumulation. 3. The timing of reactions suggested the presence of a strong regenerative mucosal response that started before the manifestation of "patchy' (grade II) mucosal reactions. 4. The regenerative response was strong enough to "make good' damage accumulated at a rate of 2 Gy/day in over a third of cases. 5. The linear quadratic model without time correction failed to provide an adequate prediction of the frequency or intensity of mucosal reactions produced by any of the regimes. A simple model of the regenerative response is presented. CONCLUSIONS: This study suggests that the timing and magnitude of the regenerative response vary between sites and individuals but are linked to the amount of epithelial cellular depletion occurring during treatment.

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PURPOSE: Mucosal underdosing as a result of electron disequilibrium at the air cavity may affect local recurrence rates for T1 and T2 larynx cancers. Secondary build-up properties of high-energy beams have been demonstrated in a slab phantom. It was the aim of this investigation to determine whether significant surface underdosing exists for the mucosa under clinical conditions. METHODS AND MATERIALS: Measurements were made using a thermoluminescent dosimetry (TLD) extrapolation technique in an anatomic larynx phantom. The larynx phantom was constructed using tissue and cartilage equivalent material, based on patient cross-sectional anatomy. Three different thicknesses of LiF ribbons, 0.14, 0.39, and 0.89 mm, were placed reproducibly at 12 different positions at the anterior, posterior, and lateral walls on the endolarynx surface. Measured doses were plotted and an extrapolation was made back to the mucosal depth to obtain the dose received at each of the positions. Results were obtained for two different field configurations, opposed laterals and oblique fields, for 6-MV X rays and opposed lateral fields from a telecesium unit. In addition, the larynx surface doses of field sizes from 4 x 6 cm2 to 7 x 6 cm2 were investigated. RESULTS: Surface underdosing was observed owing to the secondary build-up and build-down effect of the air cavity, and the dose measured for the three extrapolation TLDs at any position varied by up to 18%. An average variation of 6% was observed. The surface underdosing was most apparent for the 6-MV opposed lateral beam technique, where mucosa doses down to 76% of the prescribed dose were observed. Mucosal underdosing at the measurement positions was less marked with oblique techniques, telecesium treatment, and increasing field size. CONCLUSION: Because of underdosing, some surface positions receive < 80% of the prescribed dose. This may contribute to the potential for higher recurrence rates observed with high-energy photons.

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BACKGROUND AND PURPOSE: The erythematous response of human skin to radiotherapy has proven useful for testing the predictions of the linear quadratic (LQ) model in terms of fractionation sensitivity and repair half time. No formal investigation of the response of human skin to doses less than 2 Gy per fraction has occurred. This study aims to test the validity of the LQ model for human skin at doses ranging from 0.4 to 5.2 Gy per fraction. MATERIALS AND METHODS: Complete erythema reaction profiles were obtained using reflectance spectrophotometry in two patient populations: 65 patients treated palliatively with 5, 10, 12 and 20 daily treatment fractions (varying thicknesses of bolus, various body sites) and 52 patients undergoing prostatic irradiation for localised carcinoma of the prostate (no bolus, 30-32 fractions). RESULTS AND CONCLUSIONS: Gender, age, site and prior sun exposure influence pre- and post-treatment erythema values independently of dose administered. Out-of-field effects were also noted. The linear quadratic model significantly underpredicted peak erythema values at doses less than 1.5 Gy per fraction. This suggests that either the conventional linear quadratic model does not apply for low doses per fraction in human skin or that erythema is not exclusively initiated by radiation damage to the basal layer. The data are potentially explained by an induced repair model.

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BACKGROUND AND PURPOSES: To define new directions, the Trans Tasman Radiation Oncology Group (TROG) has conducted a detailed analysis of its unrandomised experience with radio-chemotherapy in oesophageal cancer. METHODS AND PATIENTS: Since 1984, 373 patients with oesophageal cancer have been treated on three prospective, but unrandomised, protocols involving radiation with concurrent cisplatin and infusional fluorouracil. Centres in Australia and New Zealand have contributed patients. Reasons for case selection have been examined in detail and prognostic models have been examined in the light of biases exposed. RESULTS: Cause specific survival in 92 patients treated pre-operatively with 35 Gy, infusional fluorouracil and cisplatin was 25.5 +/- 6.0% at 5 years and similar to the 5 year expectations of 169 patients treated with 60 Gy and two courses of the same chemotherapy (23.8 +/- 4.7%). Analysis of failure in these groups suggests that local relapse precedes the development of metastases and competes as a cause for ultimate failure. Although patients treated surgically were less likely to relapse locally, survival was no better because more developed metastases. Some of the 112 patients treated "palliatively" with 30-35 Gy concurrent with chemotherapy without surgery have become long-term survivors with 5 year survival figure in this group 7.7 +/- 3.4%. Apart from variables related to disease stage and performance status at presentation, tumour site emerged as a strong predictor of outcome. Prognosis worsens the nearer the tumour is to the stomach. In addition, indications of a radiation dose response relationship emerged. CONCLUSIONS: Concurrent radio-chemotherapy protocols can improve outcome in patients fit enough to tolerate these approaches. New strategies remain necessary, however.

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