Persisting Gaps in Optimal Care of Stage III Non-small Cell Lung Cancer: An Australian Patterns of Care Analysis.

BACKGROUND: Wide variation exists globally in the treatment and outcomes of stage III patients with non-small cell lung cancer (NSCLC). We conducted an up-to-date patterns of care analysis in the state of Victoria, Australia, with a particular focus on the proportion of patients receiving treatment with radical intent, treatment trends over time, and survival. MATERIALS AND METHODS: Stage III patients with NSCLC were identified in the Victorian Lung Cancer Registry and categorized by treatment received and treatment intent. Logistic regression was used to explore factors predictive of receipt of radical treatment and the treatment trends over time. Cox regression was used to explore variables associated with overall survival (OS). Covariates evaluated included age, sex, ECOG performance status, smoking status, year of diagnosis, Australian born, Aboriginal or Torres Strait Islander status, socioeconomic status, rurality, public/private status of notifying institution, and multidisciplinary meeting discussion. RESULTS: A total of 1396 patients were diagnosed between 2012 and 2019 and received treatment with radical intent 67%, palliative intent 23%, unknown intent 5% and no treatment 5%. Radical intent treatment was less likely if patients were >75 years, ECOG ≥1, had T3-4 or N3 disease or resided rurally. Surgery use decreased over time, while concurrent chemoradiotherapy and immunotherapy use increased. Median OS was 38.0, 11.1, and 4.4 months following radical treatment, palliative treatment or no treatment, respectively. CONCLUSION: Almost a third of stage III patients with NSCLC still do not receive radical treatment. Strategies to facilitate radical treatment and better support decision making between increasing multimodality options are required.

Practical considerations of single-fraction stereotactic ablative radiotherapy to the lung.

Stereotactic ablative radiotherapy (SABR) is a well-established treatment for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC) and pulmonary oligometastases. The use of single-fraction SABR in this setting is supported by excellent local control and safety profiles which appear equivalent to multi-fraction SABR based on the available data. The resource efficiency and reduction in hospital outpatient visits associated with single-fraction SABR have been particularly advantageous during the COVID-19 pandemic. Despite the increased interest, single-fraction SABR in subgroups of patients remains controversial, including those with centrally located tumours, synchronous targets, proximity to dose-limiting organs at risk, and concomitant severe respiratory illness. This review provides an overview of the published randomised evidence evaluating single-fraction SABR in primary lung cancer and pulmonary oligometastases, the common clinical challenges faced, immunogenic effect of SABR, as well as technical and cost-utility considerations.

Quality indicators for radiation oncology.

Quality Indicators, based on clinical practice guidelines, have been used in medicine and within oncology to measure quality of care for over twenty years. However, radiation oncology quality indicators are sparse. This article describes the background to the development of current national and international, general and tumour site-specific radiation oncology quality indicators in use. We explore challenges and opportunities to expand their routine prospective collection and feedback to help drive improvements in the quality of care received by people undergoing radiation therapy.

Biomarker Testing for People With Advanced Lung Cancer in England.

INTRODUCTION: Optimal management of people with advanced NSCLC depends on accurate identification of predictive markers. Yet, real-world data in this setting are limited. We describe the impact, timeliness, and outcomes of molecular testing for patients with advanced NSCLC and good performance status in England. METHODS: In collaboration with Public Health England, patients with stages IIIB to IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 0 to 2, in England, between June 2017 and December 2017, were identified. All English hospitals were invited to record information. RESULTS: A total of 60 of 142 invited hospitals in England participated in this study and submitted data on 1157 patients. During the study period, 83% of patients with advanced adenocarcinoma underwent molecular testing for three recommended predictive biomarkers (EGFR, ALK, and programmed death-ligand 1). A total of 80% of patients with nonsquamous carcinomas on whom biomarker testing was performed had adequate tissue for analysis on initial sampling. First-line treatment with a tyrosine kinase inhibitor was received by 71% of patients with adenocarcinoma and a sensitizing EGFR mutation and by 59% of those with an ALK translocation. Of patients with no driver mutation and a programmed death-ligand 1 expression of greater than or equal to 50%, 47% received immunotherapy. CONCLUSIONS: We present a comprehensive data set for molecular testing in England. Although molecular testing is well established in England, timeliness and uptake of targeted therapies should be improved.

Isotoxic Intensity Modulated Radiation Therapy in Stage III Non-Small Cell Lung Cancer: A Feasibility Study.

PURPOSE: Not all patients with stage III non-small cell lung cancer (NSCLC) are suitable for concurrent chemoradiation therapy (CRT). Local failure rate is high for sequential concurrent CRT. As such, there is a rationale for treatment intensification. METHODS AND MATERIALS: Isotoxic intensity modulated radiation therapy (IMRT) is a multicenter feasibility study that combines different intensification strategies including hyperfractionation, acceleration, and dose escalation facilitated by IMRT. Patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and unsuitable for concurrent CRT were recruited. A minimum of 2 cycles of platinum-based chemotherapy was compulsory before starting radiation therapy (RT). Radiation dose was increased until a maximum dose of 79.2 Gy was reached or 1 or more of the organs at risk met predefined constraints. RT was delivered in 1.8-Gy fractions twice daily, and an RT quality assurance program was implemented. The primary objective was the delivery of isotoxic IMRT to a dose >60 Gy equivalent dose in 2-Gy fractions (EQD2 assuming an α/ß ratio of 10 Gy for acute reacting tissues). RESULTS: Thirty-seven patients were recruited from 7 UK centers. Median age was 69.9 years (range, 46-86 years). The male-to-female ratio was 17:18. ECOG PS was 0 to 5 in 14.2% of patients; PS was 1 to 27 in 77.1% of patients; PS was 2 to 3 in 8.6% of patients. Stage IIIA:IIIB ratio was 22:13 (62.9%:37.1%). Of 37 patients, 2 (5.4%) failed to achieve EQD2 > 60 Gy. Median prescribed tumor dose was 77.4 Gy (range, 61.2-79.2 Gy). A maximum dose of 79.2Gy was achieved in 14 patients (37.8%). Grade 3 esophagitis was reported in 2 patients, and no patients developed grade 3 to 4 pneumonitis. There were 3 grade 5 events: acute radiation pneumonitis, bronchopulmonary hemorrhage, and acute lung infection. Median follow-up at time of analysis was 25.4 months (range, 8.0-44.2) months for 11 of 35 survivors. The median survival was 18.1 months (95% confidence interval [CI], 13.9-30.6), 2-year overall survival was 33.6% (95% CI, 17.9-50.1), and progression-free survival was 23.9% (95% CI, 11.3-39.1). CONCLUSIONS: Isotoxic IMRT is a well-tolerated and feasible approach to treatment intensification.

Standards of care in mesothelioma treatment.

The UK has the highest incidence of mesothelioma in the world, but services vary across the country partly due to uneven geographical distribution of cases. The Mesothelioma UK-funded national organisational audit has highlighted challenges in accessing diagnostic procedures such as thoracoscopy, as well as identifying examples of best practice, including access to clinical trials and specialist therapeutic procedures. To ensure equitable and optimal patient care, cancer alliances should have established referral pathways to specialist multidisciplinary team (MDT) services for discussion of all mesothelioma patients.

Long-Term Results from the IDEAL-CRT Phase 1/2 Trial of Isotoxically Dose-Escalated Radiation Therapy and Concurrent Chemotherapy for Stage II/III Non-small Cell Lung Cancer.

PURPOSE: The IDEAL-CRT phase 1/2 multicenter trial of isotoxically dose-escalated concurrent chemoradiation for stage II/III non-small cell lung cancer investigated two 30-fraction schedules of 5 and 6 weeks' duration. We report toxicity, tumor response, progression-free survival (PFS), and overall survival (OS) for both schedules, with long-term follow-up for the 6-week schedule. METHODS AND MATERIALS: Patients received isotoxically individualized tumor radiation doses of 63 to 71 Gy in 5 weeks or 63 to 73 Gy in 6 weeks, delivered concurrently with 2 cycles of cisplatin and vinorelbine. Eligibility criteria were the same for both schedules. RESULTS: One-hundred twenty patients (6% stage IIB, 68% IIIA, 26% IIIB, 1% IV) were recruited from 9 UK centers, 118 starting treatment. Median prescribed doses were 64.5 and 67.6 Gy for the 36 and 82 patients treated using the 5- and 6-week schedules. Grade ≥3 pneumonitis and early esophagitis rates were 3.4% and 5.9% overall and similar for each schedule individually. Late grade 2 esophageal toxicity occurred in 11.1% and 17.1% of 5- and 6-week patients. Grade ≥4 adverse events occurred in 17 (20.7%) 6-week patients but no 5-week patients. Four adverse events were grade 5, with 2 considered radiation therapy related. After median follow-up of 51.8 and 26.4 months for the 6- and 5-week schedules, median OS was 41.2 and 22.1 months, respectively, and median PFS was 21.1 and 8.0 months. In exploratory analyses, OS was significantly associated with schedule (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.32-0.98; P = .04) and fractional clinical/internal target volume receiving ≥95% of the prescribed dose (HR, 0.88; 95% CI, 0.77-1.00; P = .05). PFS was also significantly associated with schedule (HR, 0.53; 95% CI, 0.33-0.86; P = .01). CONCLUSIONS: Toxicity in IDEAL-CRT was acceptable. Survival was promising for 6-week patients and significantly longer than for 5-week patients. Survival might be further lengthened by following the 6-week schedule with an immune agent, motivating further study of such combined optimized treatments.

An evaluation of the mid-ventilation method for the planning of stereotactic lung plans.

BACKGROUND AND PURPOSE: Stereotactic ablative body radiotherapy for lung plans requires 4DCT. Most radiotherapy centres use this to determine an internal target volume (ITV), despite studies suggesting that planning on a mid-ventilation (Mid-V) phase can reduce target volumes. The purpose of this study is two-fold: to determine whether the Mid-V approach provides adequate coverage and to discuss methods to enable the Mid-V approach to be applied more widely. METHOD: 4D scans of 79 patients were outlined on every phase. The mid-V phase was identified. Margins were determined from the range of motion, and plans generated with a 55 Gy prescription. A grid-based method was used to get the probability of tumour coverage in the presence of systematic and random uncertainties, with and without blurring for breathing motion. RESULTS: For the Mid-V plans with the margins calculated from the van-Herk formula, after blurring doses for breathing, the coverage (dose covering 95% of the CTV 95% of the time) was greater than for plans with isotropic 5 mm margins uncorrected for breathing (58.2 Gy v 57.3 Gy). Similar results were obtained for a linear margin chosen as 0.15 of the breathing range. Deformable contour propagation in a commercial outlining system (ProSoma) identified the same mid-V phase in the majority of cases. CONCLUSION: Our results confirm that a mid-V approach can be used to reduce the PTV size, with no loss of tumour coverage. We propose the use of a simplified margin formula equal to the margin ignoring breathing plus 0.15 of the range of motion.

Impact of organisation and specialist service delivery on lung cancer outcomes.

INTRODUCTION: Data from the National Lung Cancer Audit (NLCA) often show variation in outcomes between lung cancer units which are not entirely explained by case mix. We explore the association between the organisation of services and patient outcome. METHODS: Details of service provision were collected via an electronic survey in June 2017. An overall organisational score derived from eleven key service factors from national lung cancer commissioning guidance was calculated for each organisation. The results for each hospital were linked to their patient outcome results from the 2015 NLCA cases. Multivariate logistic regression analysis was used to link the organisational score to patient outcomes. RESULTS: Lung cancer unit organisational audit scores varied from 0 to 11. Thirty-eight (29%) units had a score of 0-4, 64 (50%) had a score of 5-7 and 27 (21%) had a score of 8-11. Multivariate regression analysis revealed that, compared with an organisational score of 0-4, patients seen at units with a score of 8-11 had higher 1-year survival (adjusted OR (95% CI)=2.30 (1.04 to 5.08), p<0.001), higher curative-intent treatment rate (adjusted OR (95% CI)=1.62 (1.26 to 2.09), p<0.001) and greater likelihood of receiving treatment within 62 days (adjusted OR (95% CI)=1.49 (1.20 to 1.86), p<0.001). CONCLUSION: National variation in the provision of services and workforce remain. We provide evidence that adherence to the national lung commissioning guidance has the potential to improve patient outcomes within the current service structure.

Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury.

INTRODUCTION: Hepatotoxicity from T-cell checkpoint blockade is an increasingly common immune-related adverse event, but remains poorly characterised and can be challenging to manage. Such toxicity is generally considered to resemble autoimmune hepatitis, although this assumption is extrapolated from limited clinicopathological reports of anti-cytotoxic T-lymphocyte-associated protein 4-induced hepatotoxicity. METHODS: Here we report, with full clinicopathological correlation, three cases of T-cell checkpoint inhibitor-induced hepatotoxicity associated with anti-programmed cell death protein 1 agents. RESULTS: We find that a major feature of these cases is biliary injury, including a unique case of vanishing bile duct syndrome, and that such toxicity was poorly responsive to long-term immunosuppression (corticosteroids and mycophenolate mofetil). Any potential benefits of long-term immunosuppression in these cases were outweighed by therapy-related complications. DISCUSSION: We discuss potential aetiologies and risk factors for immune-mediated biliary toxicity in the context of the limited literature in this field, and provide guidance for the investigation and supportive management of affected patients.

Quantitative and textural analysis of magnetization transfer and diffusion images in the early detection of brain metastases.

PURPOSE: The sensitivity of the magnetization transfer ratio (MTR) and apparent diffusion coefficient (ADC) for early detection of brain metastases was investigated in mice and humans. METHODS: Mice underwent MRI twice weekly for up to 31 d following intracardiac injection of the brain-homing breast cancer cell line MDA-MB231-BR. Patients with small cell lung cancer underwent quarterly MRI for 1 year. MTR and ADC were measured in regions of metastasis and matched contralateral tissue at the final time point and in registered regions at earlier time points. Texture analysis and linear discriminant analysis were performed to detect metastasis-containing slices. RESULTS: Compared with contralateral tissue, mouse metastases had significantly lower MTR and higher ADC at the final time point. Some lesions were visible at earlier time points on the MTR and ADC maps: 24% of these were not visible on corresponding T2 -weighted images. Texture analysis using the MTR maps showed 100% specificity and 98% sensitivity for metastasis at the final time point, with 77% sensitivity 2-4 d earlier and 46% 5-8 d earlier. Only 2 of 16 patients developed metastases, and their penultimate scans were normal. CONCLUSIONS: Some brain metastases may be detected earlier on MTR than conventional T2 ; however, the small gain is unlikely to justify "predictive" MRI. Magn Reson Med 77:1987-1995, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer.

PURPOSE: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. PATIENTS AND METHODS: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. RESULTS: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. CONCLUSIONS: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

Three-dimensional analysis of the respiratory interplay effect in helical tomotherapy: Baseline variations cause the greater part of dose inhomogeneities seen.

PURPOSE: Dose differences from those planned can occur due to the respiratory interplay effect on helical tomotherapy. The authors present a technique to calculate single-fraction doses in three-dimensions resulting from craniocaudal motion applied to a patient CT set. The technique is applied to phantom and patient plans using patient respiratory traces. An additional purpose of the work is to determine the contribution toward the interplay effect of different components of the respiratory trace. METHODS: MATLAB code used to calculate doses to a CT dataset from a helical tomotherapy plan has been modified to permit craniocaudal motion and improved temporal resolution. Real patient traces from seven patients were applied to ten phantom plans of differing field width, modulation factor, pitch and fraction dose, and simulations made with peak-to-peak amplitudes ranging from 0 to 2.5 cm. PTV voxels near the superior or inferior limits of the PTV are excluded from the analysis. The maximum dose discrepancy compared with the static case recorded along with the proportion of voxels receiving more than 10% and 20% different from prescription dose. The analysis was repeated with the baseline variation of the respiratory trace removed, leaving the cyclic component of motion only. Radiochromic film was used on one plan-trace combination and compared with the software simulation. For one case, filtered traces were generated and used in simulations which consisted only of frequencies near to particular characteristic frequencies of the treatment delivery. Intraslice standard deviation of dose differences was used to identify potential MLC interplay, which was confirmed using nonmodulated simulations. Software calculations were also conducted for four realistic patient plans and modeling movement of a patient CT set with amplitudes informed by the observed motion of the GTV on 4DCT. RESULTS: The maximum magnitude of dose difference to a PTV voxel due to the interplay effect within a particular plan-trace combination for peak-to-peak amplitudes of up to 2.5 cm ranged from 4.5% to 51.6% (mean: 23.8%) of the dose delivered in the absence of respiratory motion. For cyclic motion only, the maximum dose differences in each combination ranged from 2.1% to 26.2% (mean: 9.2%). There is reasonable correspondence between an example of the phantom plan simulations and radiochromic film measurement. The filtered trace simulations revealed that frequencies close to the characteristic frequency of the jaw motion across the target were found to generate greater interplay effect than frequencies close to the gantry frequency or MLC motion. There was evidence of interplay between respiratory motion and MLC modulation, but this is small compared with the interplay between respiratory motion and jaw motion. For patient-plan simulations, dose discrepancies are seen of up to 9.0% for a patient with 0.3 cm peak-to-peak respiratory amplitude and up to 17.7% for a patient with 0.9 cm peak-to-peak amplitude. These values reduced to 1.3% and 6.5%, respectively, when only cyclic motion was considered. CONCLUSIONS: Software has been developed to simulate craniocaudal respiratory motion in phantom and patient plans using real patient respiratory traces. Decomposition of the traces into baseline andcyclic components reveals that the large majority of the interplay effect seen with the full trace is due to baseline variation during treatment.

Accelerated hypo-fractionated radiotherapy for non small cell lung cancer: results from 4 UK centres.

BACKGROUND AND PURPOSE: A variety of radiotherapy fractionations are used as potentially curative treatments for non-small cell lung cancer. In the UK, 55 Gy in 20 fractions over 4 weeks (55/20) is the most commonly used fractionation schedule, though it has not been validated in randomized phase III trials. This audit pooled together existing data from 4 UK centres to produce the largest published series for this schedule. MATERIALS AND METHODS: 4 UK centres contributed data (Cambridge, Cardiff, Glasgow and Sheffield). Case notes and radiotherapy records of radically treated patients between 1999 and 2007 were retrospectively reviewed. Basic patient demographics, tumour characteristics, radiotherapy and survival data were collected and analysed. RESULTS: 609 patients were identified of whom 98% received the prescribed dose of 55/20. The median age was 71.3 years, 62% were male. 90% had histologically confirmed NSCLC, 49% had stage I disease. 27% had received chemotherapy (concurrent or sequential) with their radiotherapy. The median overall survival from time of diagnosis was 24.0 months and 2 year overall survival was 50%. CONCLUSION: These data show respectable results for patients treated with accelerated hypo-fractionated radiotherapy for NSCLC with outcomes comparable to those reported for similar schedules and represent the largest published series to date for 55/20 regime.

Optimal use of a panel of methylation markers with GSTP1 hypermethylation in the diagnosis of prostate adenocarcinoma.

PURPOSE: In this study, we tested the ability of a panel of hypermethylation markers to improve the sensitivity of histologic prostate cancer detection in sextant needle biopsies. EXPERIMENTAL DESIGN: We obtained fresh-frozen sextant biopsies from 72 excised prostates and directly compared blinded histologic review and quantitative real-time methylation-specific PCR for hypermethylation of four genes, Tazarotene-induced gene 1 (TIG1), adenomatous polyposis coli (APC), retinoic acid receptor beta2 (RARbeta2), and glutathione S-transferase pi (GSTP1) to detect the presence of prostate cancer. Results were compared with the final surgical pathological review of the resected prostates as the gold standard. RESULTS: Histologic review alone detected carcinoma with a sensitivity of 64% (39 of 61 cases) and 100% specificity. Quantitative real-time methylation-specific PCR for TIG1, APC, RARbeta2, and GSTP1 detected carcinoma with a sensitivity of 70%, 79%, 89%, and 75%, respectively, with 100% specificity for all of the genes. Using this panel of methylation markers in combination with histology resulted in the detection of 59 of 61 (97%) cases of prostate with 100% specificity, a 33% improvement over histology alone. CONCLUSION: The use of a panel of methylation markers as an adjunct to histologic review may substantially augment prostate cancer diagnosis from needle biopsies.

Real-time gap ligase chain reaction: a rapid semiquantitative assay for detecting p53 mutation at low levels in surgical margins and lymph nodes from resected lung and head and neck tumors.

PURPOSE: We have developed a real-time semiquantitative gap ligase chain reaction for detecting p53 point mutations at low level in a background of excess of wild-type DNA. EXPERIMENTAL DESIGN: This method was validated by direct comparison to a previously validated but cumbersome phage plaque hybridization assay. Forty-one surgical margins and lymph nodes from 10 cases of head and neck squamous cell carcinoma and lung carcinoma were tested for p53 mutant clones. RESULTS: Both methods detected p53 mutants in margins from 8 of the 10 cases, whereas standard pathology detected cancer cells in only 3 cases. Positive margins included tissue samples with a tumor/normal DNA ratio of up to 1:1000. CONCLUSIONS: This novel molecular approach can be performed in <5 h facilitating intraoperative use for real-time surgical resection.

A method for reducing ovarian doses in whole neuro-axis irradiation for medulloblastoma.

BACKGROUND AND PURPOSE: Cranio-spinal irradiation for medulloblastoma can impair fertility in girls. The literature indicates that an ovarian dose of 4 Gy causes permanent infertility in 30% of young females and that doses of <1.5 Gy over the whole treatment are desirable. We report a modified radiotherapy technique using a non-divergent beam edge inferiorly to reduce the ovarian dose. PATIENTS AND METHODS: Eight female patients with medulloblastoma had magnetic resonance imaging (MRI) studies in the treatment position to identify the position of their ovaries relative to the radiation field. The information was transferred to the radiotherapy planning system and plans were generated using conventional spinal fields and modified fields with a half beam block at the inferior border. RESULTS: Identifying the position of the ovaries by MRI enabled the dose to be estimated for the two techniques. Using a non-divergent beam inferiorly, the mean ovarian dose was reduced in all cases by a median value of 2.45 Gy (range 0.6-19.5 Gy) and the median percentage reduction was 66.8% (range 2.6-84.6%). The position of the ovary relative to the beam edge was critical in determining the dose reduction for each case. The modified technique doubled the number of patients receiving <4 Gy to a single ovary from three to six. With this alteration, three patients also had an ovary receiving <1.5 Gy whereas all exceeded this dose with conventional treatment. CONCLUSION: We recommend using asymmetry at the inferior spinal border to achieve a non-divergent edge to the treatment field to reduce the dose to the ovary. Using MRI to localise the ovaries is important in estimating their dose and in assisting the counselling of patients and their families about future fertility.

Quantitative assessment of inter-clinician variability of target volume delineation for medulloblastoma: quality assurance for the SIOP PNET 4 trial protocol.

BACKGROUND AND PURPOSE: To assess inter-clinician variability amongst specialist paediatric radiation oncologists in delineating clinical target volumes for treating medulloblastoma as a quality assurance exercise prior to the introduction of the SIOP PNET 4 trial protocol of conformal radiotherapy to the posterior fossa and tumour bed. PATIENTS AND METHODS: Participants from 17 UK centres attended an educational meeting and then completed a clinical planning exercise to outline: (1) the whole posterior fossa and (2) the tumour bed. Quantitative analysis of the volumes, lengths, spatial positioning and axial planes for each individual was carried out and variation between individuals analysed. RESULTS: Outlining of the posterior fossa was reasonably consistent, although most variation was seen in defining the superior border of the tentorium. A major difference was the decision whether or not to include the post-surgical meningocoele in the clinical target volume (CTV). The CTV for the tumour bed was under treated by all participants due to lack of inclusion of pre-operative tumour extent. CONCLUSIONS: This exercise demonstrated several ambiguities in the draft protocol and highlighted particular areas of inter-clinician variation. Consequently the protocol was revised and improved to take account of these findings. We recommend that planning exercises, in conjunction with education and training, should be implemented before the start of any new radiotherapy trial. In the future, the use of image transfer will allow prospective peer review of target volumes before treatment commences. These measures are essential to ensure that alterations in clinical practice are achieved in a uniform way.

Quantitative GSTP1 methylation and the detection of prostate adenocarcinoma in sextant biopsies.

Hypermethylation of the 5' promoter region of the glutathione S-transferase pi gene (GSTP1) occurs at a very high frequency in prostate adenocarcinoma. We compared the results of blinded histologic review of sextant biopsy samples from 72 excised prostates with those obtained using a quantitative methylation-specific polymerase chain reaction assay (QMSP) for GSTP1. Formal surgical pathologic review of the resected prostates was used to determine the number of patients with (n = 61) and without (n = 11) prostate cancer. Histology alone detected prostate carcinoma with 64% sensitivity (95% confidence interval [CI] = 51% to 76%) and 100% specificity (95% CI = 72% to 100%), whereas the combination of histology and GSTP1 QMSP at an assay threshold greater than 10 detected prostate carcinoma with 75% sensitivity (95% CI = 63% to 86%) and 100% specificity (95% CI = 72% to 100%), an 11% improvement (95% CI = 5% to 22%) in sensitivity over histology alone. The combination of histology and GSTP1 QMSP at an assay threshold greater than 5 detected prostate adenocarcinoma with 79% sensitivity (95% CI = 68% to 89%), a 15% improvement (95% CI = 7% to 26%) over histology alone. Thus, GSTP1 QMSP improved the sensitivity of histologic review of random needle biopsies for prostate cancer diagnosis. Further studies should determine whether detection of GSTP1 hypermethylation in a biopsy sample with normal histology indicates the need for an early repeat biopsy at the same site.