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The limited radiation tolerance of the small-bowel causes toxicity for patients receiving conventionally-fractionated radiotherapy for rectal cancer. Safe radiotherapy dose-escalation will require a better understanding of such toxicity. We conducted a systematic review and meta-analysis using published datasets of small bowel dose-volume and outcomes to analyse the relationship with acute toxicity. SCOPUS, EMBASE & MEDLINE were searched to identify twelve publications reporting small-bowel dose-volumes and toxicity data or analysis. Where suitable data were available (mean absolute volume with parametric error measures), fixed-effects inverse-variance meta-analysis was used to compare cohorts of patients according to Grade ≥3 toxicity. For other data, non-parametric examinations of irradiated small-bowel dose-volume and incidence of toxicity were conducted, and a univariate logistic regression model was fitted. On fixed-effects meta-analysis of three studies (203 patients), each of the dose-volume measures V5Gy-V40Gy were significantly greater (p

Background: In LAPC, additional benefit of CRT over chemotherapy is uncertain. Optimising local therapy for a subset that never develops distant disease may prolong survival. Nelfinavir is thought to enhance radiosensitivity through hypoxia reduction by increasing tumour blood flow. Methods: A non-randomised, single centre phase II study, in FDG-PET-selectedpatients withhistologically proven LAPC. CRT consisted of: nelfinavir 1250 mg bd (days -3 to 45); gemcitabine 300 mg/m2 & cisplatin 30 mg/m2 (days 2, 9, 23 & 30); concurrent radiotherapy: 59.4 Gy/33# to primary tumour, 50.4 Gy/28# to regional nodes. Adjuvant gemcitabine was given for 6 months. Primary endpoint: 1 year overall survival (OS); secondary endpoints included: toxicity, response rate, resectability, median progression free survival (PFS), OS and local PFS. 6 patients had sequential dynamic 18fluoromisonidazole PET (FMISO-PET) and perfusion CT (pCT) before and after 6-7 days of nelfinavir (given from day -8). Results: 23 patients entered between Feb 2010-July2014. The trial was stopped because of unavailability of nelfinavir in Europe. 3 patients did not complete treatment (1 each of PE, biliary sepsis, stroke). Common G3/4 toxicities: thrombocytopenia/leukopenia (both 35%), diarrhoea (17%), nausea/vomiting (17%), fatigue (13%). 1 yr and median OS: 76.7% (95% CI 52.8-89.6) and 17.4 months (95% CI 12.7-22.8) respectively. 1 yr PFS and Local PFS: 36.8% (16.5-57.5) and 52.9% (95% CI 25.2-74.4) respectively. Mean FDG SUVmax reduction was 39% (p < 0.001) and was ≥60% in 29% of patients. 2 patients became resectable. 4/6 patients had reduced FMISO retention and increased pCT derived blood flow (BF) post-nelfinavir. Mean change in FMISO-k3 (2 tissue compartmental model) -50.3% vs 6% and BF 20.1 vs -7.1% in responders vs non-responders. 8/13 demonstrated a reduction in pAKT in peripheral blood mononuclear cells. Conclusions: Nelfinavir with CRT is well tolerated with promising outcomes, as these patients were not pre-selected through induction chemotherapy. Modulation of hypoxia & BF by nelfinavir was demonstrated. A randomised phase II study, SCALOP2, opens in 2015. Clinical trial information: 2008-006302-42.

Purpose: Tumor vessels influence the growth and response of tumors to therapy. Imaging vascular changes in vivo using dynamic contrast-enhanced MRI (DCE-MRI) has shown potential to guide clinical decision making for treatment. However, quantitative MR imaging biomarkers of vascular function have not been widely adopted, partly because their relationship to structural changes in vessels remains unclear. We aimed to elucidate the relationships between vessel function and morphology in vivo. Experimental Design: Untreated preclinical tumors with different levels of vascularization were imaged sequentially using DCE-MRI and CT. Relationships between functional parameters from MR (iAUC, Ktrans, and BATfrac) and structural parameters from CT (vessel volume, radius, and tortuosity) were assessed using linear models. Tumors treated with anti-VEGFR2 antibody were then imaged to determine whether antiangiogenic therapy altered these relationships. Finally, functional–structural relationships were measured in 10 patients with liver metastases from colorectal cancer. Results: Functional parameters iAUC and Ktrans primarily reflected vessel volume in untreated preclinical tumors. The relationships varied spatially and with tumor vascularity, and were altered by antiangiogenic treatment. In human liver metastases, all three structural parameters were linearly correlated with iAUC and Ktrans. For iAUC, structural parameters also modified each other's effect. Conclusions: Our findings suggest that MR imaging biomarkers of vascular function are linked to structural changes in tumor vessels and that antiangiogenic therapy can affect this link. Our work also demonstrates the feasibility of three-dimensional functional–structural validation of MR biomarkers in vivo to improve their biological interpretation and clinical utility. Clin Cancer Res; 24(19); 4694–704. ©2018 AACR.

Aims\ud \ud \ud Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC).\ud \ud \ud \ud Materials and methods\ud \ud \ud Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose–volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade ≥2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade ≥2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression.\ud \ud \ud \ud Results\ud \ud \ud CTCAE grade ≥2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V35–45Gy was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007–1.063) and grade (1.023, 1.003–1.044) of toxicity. The area under the curve was 0.632 (0.516–0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm3). Using a threshold of 30 cm3, risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V35–45Gy. Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274–12.342) and weight loss during induction chemotherapy (1.216, 1.043–1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015–1.780). Duodenum dose–volume did not predict toxicity risk or severity in any cohort.\ud \ud \ud \ud Conclusions\ud \ud \ud In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35–45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents.

Background and purpose A recent update of the RTOG 9811, reported differing relapse rates for early and late anal squamous cell carcinoma following chemoradiotherapy (CRT). There may be a role for dose-individualization, however the dose–response relationship for anal cancer is not currently known. Intensity-modulated radiotherapy (IMRT) has been widely adopted with multiple series published. The aim is to fit a tumor control probability (TCP) model to the published IMRT data. Materials and methods We performed a systematic review of PubMed and Embase databases to identify thirteen appropriate papers, including 625 patients. Predefined data fields were collected. A standard linear quadratic TCP model, which included repopulation, was fit by least squares minimization. Results The fitted TCP curve demonstrated a dose–response relationship with α = 0.196 Gy–1. The curve suggests: in early stage tumours, a dose reduction from 50 Gy to 45 Gy reduces 2 year local control from 98% to 95%; in late stage tumours, a dose escalation from 50 Gy to 55 Gy improves the 2 year local control rate from approximately 50% to 80%. Conclusions The published data are broadly consistent with a linear quadratic dose–response model. Dose-individualization in anal cancer should be further investigated in the context of clinical trials.

Functional imaging gives information about physiological heterogeneity in tumours. The utility of functional imaging tests in providing predictive and prognostic information after chemoradiotherapy for both oesophageal cancer and pancreatic cancer will be reviewed. The benefit of incorporating functional imaging into radiotherapy planning is also evaluated. In cancers of the upper gastrointestinal tract, the vast majority of functional imaging studies have used 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Few studies in locally advanced pancreatic cancer have investigated the utility of functional imaging in risk-stratifying patients or aiding target volume definition. Certain themes from the oesophageal data emerge, including the need for a multiparametric assessment of functional images and the added value of response assessment rather than relying on single time point measures. The sensitivity and specificity of FDG-PET to predict treatment response and survival are not currently high enough to inform treatment decisions. This suggests that a multimodal, multiparametric approach may be required. FDG-PET improves target volume definition in oesophageal cancer by improving the accuracy of tumour length definition and by improving the nodal staging of patients. The ideal functional imaging test would accurately identify patients who are unlikely to achieve a pathological complete response after chemoradiotherapy and would aid the delineation of a biological target volume that could be used for treatment intensification. The current limitations of published studies prevent integrating imaging-derived parameters into decision making on an individual patient basis. These limitations should inform future trial design in oesophageal and pancreatic cancers.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

Purpose\ud Using radiobiological modelling to estimate normal tissue toxicity, this study investigates the effects of dose escalation for concurrent chemoradiation therapy (CRT) in lower third oesophageal tumours on the stomach.\ud \ud Methods and materials\ud 10 patients with lower third oesophageal cancer were selected from the SCOPE 1 database (ISCRT47718479) with a mean planning target volume (PTV) of 348 cm3. The original 3D conformal plans (50Gy3D) were compared to newly created RapidArc plans of 50GyRA and 60GyRA, the latter using a simultaneous integrated boost (SIB) technique using a boost volume, PTV2. Dose-volume metrics and estimates of normal tissue complication probability (NTCP) were compared.\ud \ud Results\ud There was a significant increase in NTCP of the stomach wall when moving from the 50GyRA to the 60GyRA plans (11–17 %, Wilcoxon signed rank test, p = 0.01). There was a strong correlation between the NTCP values of the stomach wall and the volume of the stomach wall/PTV 1 and stomach wall/PTV2 overlap structures (R = 0.80 and R = 0.82 respectively) for the 60GyRA plans.\ud \ud Conclusion\ud Radiobiological modelling suggests that increasing the prescribed dose to 60Gy may be associated with a significantly increased risk of toxicity to the stomach. It is recommended that stomach toxicity be closely monitored when treating patients with lower third oesophageal tumours with 60Gy.

BACKGROUND: The goal of the current study was to investigate the tumor control probability (TCP) of advanced radiotherapy technologies for stage III non-small cell lung cancer (NSCLC) and to evaluate potential interplay effects between their applications. MATERIALS AND METHODS: Three-dimensional conformal radiotherapy (3D-CRT) with conventionally fractionated doses of 66 Gy served as reference for 13 patients with stage III NSCLC. Isotoxic dose escalation relative to the corresponding 3D-CRT plans was performed for three technologies and their combinations: intensity-modulated radiotherapy (IMRT), IMRT with a simultaneous integrated boost (IMRT-SIB) of 10% to the gross tumor volume (GTV), and adaptive re-planning twice during the treatment course (ART). All analyses were based on accumulated dose distributions using deformable image registration of CT images, which were acquired weekly during the treatment course. RESULTS: IMRT reduced the mean lung dose (MLD) by 5.6% ± 3.8% compared to 3D-CRT. ART resulted in lung sparing of 7.9% ± 4.8% and 9.2% ± 3.9% in 3D-CRT and IMRT planning, respectively. IMRT and ART escalated the irradiation dose by 6.6% ± 3.2% and 8.8% ± 6.3%, respectively, which was not statistically different. For the 7 patients with the largest GTVs, IMRT-SIB was superior to IMRT and ART with dose escalation of 11.9% ± 3.7%. The combination of ART, IMRT, and SIB achieved maximum dose escalation in all 13 patients by 17.1% ± 5.4% on average, which increased TCP from 19.9% ± 7.0 to 37.1% ± 10.1%. Adaptive re-planning was required to continuously conform the escalated and hypofractionated SIB doses to the shrinking tumor. CONCLUSION: Combining advanced radiotherapy technologies is considered as a safe and effective strategy to maximize local tumor control probability in stage III NSCLC.

PURPOSE: This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. METHODS AND MATERIALS: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm(3). A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA62.5) was compared to a standard dose plan of 50 Gy/25 fractions (RA50). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. RESULTS: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA50) to 56.3% (RA62.5), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA50) versus 5.6% (RA62.5) P

Background An unexpected finding from the phase III parotid sparing radiotherapy trial, PARSPORT (ISRCTN48243537, CRUK/03/005), was a statistically significant increase in acute fatigue for those patients who were treated with intensity-modulated radiotherapy (IMRT) compared to standard conventional radiotherapy (CRT). One possible explanation was the difference in dose to central nervous system (CNS) structures due to differing beam portals. Using data from the trial, a dosimetric analysis of individual CNS structures was performed. Method Dosimetric and toxicity data were available for 67 patients (27 CRT, 40 IMRT). Retrospective delineation of the posterior fossa, brainstem, cerebellum, pituitary gland, pineal gland, hypothalamus, hippocampus and basal ganglia was performed. Dosimetry was reviewed using summary statistics and dose–volume atlases. Results A statistically significant increase in maximum and mean doses to each structure was observed for patients who received IMRT compared to those who received CRT. Both maximum and mean doses were significantly higher for the posterior fossa, brainstem and cerebellum for the 42 patients who reported acute fatigue of Grade 2 or higher ( p ⩽0.01) compared to the 25 who did not. Dose–volume atlases of the same structures indicated that regions representing larger volumes and higher doses to each structure were consistent with a higher incidence of acute fatigue. There was no association between the dose distribution and acute fatigue for the other structures tested. Conclusions The excess fatigue reported in the IMRT arm of the trial may, at least in part, be attributed to the dose distribution to the posterior fossa, cerebellum and brainstem. Future studies that modify dose delivery to these structures may allow us to test the hypothesis that radiation-induced fatigue is avoidable.

Pancreatic adenocarcinoma patients have a poor prognosis, with the fi ve-year overall survival rate 5% [1]. Treatment options for these patients may include pre-operative or defi nitive chemo-radiotherapy (CRT). Patterns of failure suggest that inclusion of elective lymph nodes in the treatment volume may improve local control [2]. These extended volumes, in conjunction with large margins to account for breathing motion, generate substantial planning treatment volumes (PTV) which may increase the risk of gastro-intestinal (GI) toxicity. Several publications have investigated the use of intensity-modulated radiotherapy (IMRT) [3 – 7] and intensity-modulated arc therapy (IMAT) [8 – 11] for treatment of pancreatic cancer, where the improved dose conformation may reduce dose to surrounding normal tissue, and allow dose escalation for improved local control. Despite studies showing a correlation between dosimetric parameters and GI toxicity for three-dimensional (3D)-RT and IMRT [12] there is some debate over dose constraints for stomach, duodenum and small bowel. Differences in organ delineation and prescribed dose may limit the comparison of dose-volume histogram (DVH) parameters, and a standard dose-volume analysis is often limited to only a few points in the DVH data, which may not always correspond directly to a clinical outcome. However, radiobiological modelling evaluates treatment plans by analysing the entire DVH and reducing this multifactorial comparison into a single clinically relevant parameter. As the parameters used for modelling normal tissue complication probability (NTCP) are derived from observed rates of toxicity in clinical trials, these parameters should be cited as a range of values (e.g. covering a 95% confi dence interval). Each parameter set is specifi c for a selected endpoint and is also dependent on the patient cohort and the treatment technique used. Careful comparison of the predicted complications with observed clinical toxicity is required to validate each set of NTCP parameters which may be found in the literature [13]. Nonetheless, radiobiological modelling may be useful for assessing different planning techniques and dose prescriptions, and has been applied to compare predicted toxicity to stomach and duodenum for a dose escalation study using tomotherapy plans for pancreatic cancer [5]. The current study compares the use of NTCP models and dose-volume metrics to analyse RapidArc (IMAT) and three-dimensional conformal treatment (3D-RT) plans for locally-advanced pancreatic cancer (LAPC). Using commercially available biological evaluation software module (Eclipse, Varian, Palo Alto

A review of the technical aspects of high-dose hypofractionated radiotherapy for localised non-small cell lung cancer was carried out to allow correlation with outcome measures and with a consensus view of the technique. A Pubmed search carried out between January 2001 and April 2007 identified 15 studies for inclusion. The clinical and technical aspects of treatment were extracted and their effect on survival, progression-free survival and toxicity were assessed using the summary statistic of weighted means. A comparison was made with the RTOG 0236 consensus study protocol. The range of variables in the studies precluded correlation of outcome with tumour parameters, dose fractionation and technical aspects such as immobilisation, techniques dealing with breathing motion, beam number and arrangement and organ at risk dose constraints. Robust data to justify a consensus view were not found, which suggests that further studies are required. They should focus on developing the treatment technique of stereotactic body radiation therapy for early-stage non-small cell lung cancer and correlating it with outcome to provide a rational basis for future randomised trials, comparing the technique with conformal radiotherapy and surgery, and the introduction of the technique into routine clinical practice.

PurposeThe optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy.Methods and MaterialsEligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled.Results3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, higher versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P

Aims The potential advantages of stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC) over conventional fractionated radiotherapy include a higher biological effective dose, a reduction in accelerated repopulation, greater patient convenience and reduced demand on radiotherapy resources. Before introducing SBRT in our department, a review of planning and delivery was undertaken, starting with an assessment of optimum beam number and arrangement. Materials and methods Radiotherapy planning computed tomography scans for five patients previously treated for T1 peripheral NSCLC were selected. In each the contoured tumour had planning target volume (PTV) margins of 1cm in all directions. Forward-planned three-field coplanar and non-coplanar plans and a seven-field coplanar plan were produced and optimised. In-house inverse-planning software (AutoBeam) was used to generate three-, five-, seven- and nine-field coplanar and non-coplanar plans and two volumetric intensity-modulated arc therapy (VMAT) plans. The resulting V 20 , V 11 , PTV 90 , PTV 95 and mean lung dose were compared. Results Analysis of variance showed non-coplanar plans to have lower V 11 and higher PTV 90 and PTV 95 than coplanar plans. VMAT showed equivalent V 20 and target coverage when compared with the best non-coplanar plans, but with a faster delivery time (2min 8s versus 12min 40s). Conclusions Inverse-planned five-field non-coplanar plans and VMAT improve target coverage while minimising the higher dose to normal lung tissue for SBRT of NSCLC compared with coplanar beam arrangements. VMAT is preferable because of significantly shorter treatment delivery times.

Purpose To review the published clinical data on non-small cell lung cancer treated with radical radiotherapy to confirm a dose–response relationship as a basis for further dose-escalation trials. Methods Twenty-four published clinical trials were identified, 16 of which – with 29 different standard, hyper- and hypofractionated treatment schedules – were analysed. Prescription doses were converted to biologically-equivalent dose (BED), with a correction for repopulation. Disease-free survival data were corrected for the stage profile of each cohort to allow better comparison of results. We also analysed moderate (grade II and III) lung and oesophageal acute toxicity related to the corrected BED delivered to the tumour. Results The clinical data analysed showed good agreement between the observed and modelled disease-free survival at 2years when compared to the published models of Fenwick (correlation coefficient 0.525, p =0.003) and Martel (correlation coefficient 0.492, p =0.007), indicating a clear tumour dose–response. In the normally fractionated treatments (∼2Gy per fraction), improved disease-free survival was generally observed in the shorter schedules (maximum around 6weeks). However, the best outcomes were obtained for the hypofractionated schedules. No systematic relationship was seen between prescribed dose and lung or oesophageal acute toxicity, possibly due to dose selection depending on V 20 or MLD in some studies and the diversity of the patients analysed. Conclusions We have demonstrated a dose–response relationship for NSCLC based on clinical data. The clinical data provide a rational basis for selection of dose escalation schedules to be tested in future randomised trials.

There is growing clinical evidence that functional imaging is useful for target volume definition and early assessment of tumour response to external beam radiotherapy. A subject that has perhaps received less attention, but is no less promising, is the application of functional imaging to the prediction or measurement of radiation adverse effects in normal tissues. In this manuscript, we review the current published literature describing the use of positron emission tomography (PET), four-dimensional computed tomography (4D-CT), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) to study normal tissue function in the context of radiotherapy to the lung, liver and head & neck. Published results to date demonstrate that functional imaging can be used to preferentially avoid normal tissues not easily identifiable on solely anatomical images. It is also a potentially very powerful tool for the early detection of radiotherapy-induced normal tissue adverse effects and could provide valuable data for building predictive models of outcome. However, one of the major challenges to building useful predictive models is that, to date, there are very little data available with combined images of normal function, 3D delivered radiation dose and clinical outcomes. Prospective data collection through well-constructed studies which use established morbidity scores is clearly a priority if significant progress is to be made in this area.

Background and purpose The study aimed to examine specific avoidance of functional lung (FL) defined by a single photon emission computerized tomography (SPECT) lung perfusion scan, using intensity modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3-DCRT) in patients with non-small cell lung cancer (NSCLC). Materials and methods Patients with NSCLC underwent planning computerized tomography (CT) and lung perfusion SPECT scan in the treatment position using fiducial markers to allow co-registration in the treatment planning system. Radiotherapy (RT) volumes were delineated on the CT scan. FL was defined using co-registered SPECT images. Two inverse coplanar RT plans were generated for each patient: 4-field 3-DCRT and 5-field step-and-shoot IMRT. 3-DCRT plans were created using automated AutoPlan optimisation software, and IMRT plans were generated employing Pinnacle 3 treatment planning system (Philips Radiation Oncology Systems). All plans were prescribed to 64Gy in 32 fractions using data for the 6MV beam from an Elekta linear accelerator. The objectives for both plans were to minimize the volume of FL irradiated to 20Gy (fV 20 ) and dose variation within the planning target volume (PTV). A spinal cord dose was constrained to 46Gy. Volume of PTV receiving 90% of the prescribed dose (PTV 90 ), fV 20 , and functional mean lung dose (fMLD) were recorded. The PTV 90 /fV 20 ratio was used to account for variations in both measures, where a higher value represented a better plan. Results Thirty-four RT plans of 17 patients with stage I–IIIB NSCLC suitable for radical RT were analysed. In 6 patients with stage I–II disease there was no improvement in PTV 90 , fV 20 , PTV/fV 20 ratio and fMLD using IMRT compared to 3-DCRT. In 11 patients with stage IIIA–B disease, the PTV was equally well covered with IMRT and 3-DCRT plans, with IMRT producing better PTV 90 /fV 20 ratio (mean ratio – 7.2 vs. 5.3, respectively, p =0.001) and reduced fMLD figures compared to 3-DCRT (mean value – 11.5 vs. 14.3Gy, p =0.001). This was due to reduction in fV 20 while maintaining PTV coverage. Conclusion The use of IMRT compared to 3-DCRT improves the avoidance of FL defined by perfusion SPECT scan in selected patients with locally advanced NSCLC. If the dose to FL is shown to be the primary determinant of lung toxicity, IMRT would allow for effective dose escalation by specific avoidance of FL.

Activity quantification in nuclear medicine imaging is highly desirable, particularly for dosimetry and biodistribution studies of radiopharmaceuticals. Quantitative (111)In imaging is increasingly important with the current interest in therapy using (90)Y radiolabeled antibodies. One of the major problems in quantification is scatter in the images, which leads to degradation of image quality. The aim of this study was to optimize the energy-window settings for quantitative (111)In imaging with a camera that enabled acquisition in three energy windows. Experimental measurements and Monte Carlo simulations, using the SI-MIND code, were conducted to investigate parameters such as sensitivity, image contrast, and image resolution. Estimated scatter-to-total ratios and distributions, as obtained by the different window settings, were compared with corresponding simulations. Results showed positive agreement between experimental measurements and results from simulations, both quantitatively and qualitatively. We conclude that of the investigated methods, the optimal energy-window setting was two windows centered at 171 and 245 keV, together with a broad scatter window located between the photopeaks.

Background and purpose Patients with non-small cell lung cancer (NSCLC) often have inhomogeneous lung perfusion. Radiotherapy planning computed tomography (CT) scans have been accurately co-registered with lung perfusion single photon emission computed tomography (SPECT) scans to design radiotherapy treatments which limit dose to healthy ‘perfused' lung. Patients and methods Patients with localised NSCLC had CT and SPECT scans accurately co-registered in the planning system. The SPECT images were used to define a volume of perfused ‘functioning' lung (FL). Inverse planning software was used to create 3D-conformal plans, the planning objective being either to minimise the dose to whole lungs (WL) or to minimise the dose to FL. Results Four plans were created for each of six patients. The mean difference in volume between WL and FL was 1011.7cm 3 (range 596.2–1581.1cm 3 ). One patient with bilateral upper lobe perfusion deficits had a 16% reduction in FLV 20 (the percentage volume of functioning lung receiving ≥20Gy). The remaining patients had inhomogeneous perfusion deficits such that inverse planning was not able to sufficiently optimise beam angles to avoid functioning lung. Conclusion SPECT perfusion images can be accurately co-registered with radiotherapy planning CT scans and may be helpful in creating treatment plans for patients with large perfusion deficits.

Background and purpose To investigate the feasibility and the advantages of a portal-imaging mode on a medical accelerator, consisting of a thin low-Z bremsstrahlung target and a thin Gd 2 O 2 S/film detector, for patient imaging. Patients and methods The international code of practice for high-energy photon dosimetry was used to calibrate dosimetry instruments for the imaging beam produced by 4.75MeV electrons hitting a 6mm thick aluminium target. Images of the head and neck of a humanoid phantom were taken with a mammography film system and the dose in the phantom was measured with TLDs calibrated for this beam. The first head and neck patient images are compared with conventional images (taken with the treatment beam on a film radiotherapy verification detector). Visibility of structures for six patients was evaluated. Results Images of the head and neck of a humanoid phantom, taken with both imaging systems showed that the contrast increased dramatically for the new system while the dose required to form an image was less than 10 −2 Gy. The patient images taken with the new and the conventional systems showed that air–tissue interfaces were better defined in the new system image. Anatomical structures, visible on both films, are clearer with the new system. Additionally, bony structures, such as vertebrae, were clearly visible only with the new system. The system under evaluation was significantly better for all features in lateral images and most features in anterior images. Conclusions This pilot study of the new portal imaging system showed the image quality is significantly improved.

Gastrointestinal (GI) toxicity impedes dose escalation and likelihood of cure in chemoradiotherapy (CRT) for hepatobiliary malignancies. The risk of toxicity can depend on clinical and radiotherapy (RT) dose-volume metrics. We aimed to identify predictive factors using data from two prospective phase-II clinical trials of locally-advanced pancreatic cancer (LAPC).

AIM: To investigate systematic changes in dose arising when treatment plans optimised using the Anisotropic Analytical Algorithm (AAA) are recalculated using Acuros XB (AXB) in patients treated with definitive chemoradiotherapy (dCRT) for locally advanced oesophageal cancers. BACKGROUND: We have compared treatment plans created using AAA with those recalculated using AXB. Although the Anisotropic Analytical Algorithm (AAA) is currently more widely used in clinical routine, Acuros XB (AXB) has been shown to more accurately calculate the dose distribution, particularly in heterogeneous regions. Studies to predict clinical outcome should be based on modelling the dose delivered to the patient as accurately as possible. METHODS: CT datasets from ten patients were selected for this retrospective study. VMAT (Volumetric modulated arc therapy) plans with 2 arcs, collimator rotation ± 5-10° and dose prescription 50 Gy / 25 fractions were created using Varian Eclipse (v10.0). The initial dose calculation was performed with AAA, and AXB plans were created by re-calculating the dose distribution using the same number of monitor units (MU) and multileaf collimator (MLC) files as the original plan. The difference in calculated dose to organs at risk (OAR) was compared using dose-volume histogram (DVH) statistics and p values were calculated using the Wilcoxon signed rank test. The potential clinical effect of dosimetric differences in the gross tumour volume (GTV) was evaluated using three different TCP models from the literature. RESULTS: PTV Median dose was apparently 0.9 Gy lower (range: 0.5 Gy - 1.3 Gy; p

Purpose/objective: To analyse outcome and toxicity of stereotactic body radiotherapy (SBRT) in pancreatic cancer (PDAC). Material/methods: We systematically reviewed full reports on outcome and toxicity transforming prescription doses to equivalent doses of 2Gy (EQD2) and biological equivalent doses (BED). Pearson product-moment correlation coefficient, regression analysis and Lyman–Kutcher–Burman modelling were used. Results: Sixteen trials (572 patients) were identified. Local control correlated with dose. Additionally 4 upper gastrointestinal-SBRT trials (149 patients) were included for toxicity analysis. Acute toxicity was mild but late toxicity ⩾G2 was substantial and predominantly gastrointestinal. Late toxicity ⩾G2 and ⩾G3 correlated highly with EQD2/BED after linear ( R 2 =0.85 and 0.77, respectively) and Lyman–Kutcher–Burman modelling. Linear regression lines indicated ⩾G2 and ⩾G3 toxicity frequencies of 5% at 65Gy and 80Gy EQD2-α/β=3, respectively. A comparison of toxicity with dose constraints for duodenum revealed partly inadequate dose constraints. Conclusion: Results from multiple fraction regimens could be successfully interpreted to estimate toxicity according to EQD2/BED prescription doses, and dose constraints for the duodenum were derived, whereas local control appeared to be less dose-dependent. This analysis may be useful to plan clinical trials for SBRT and hypofractionated radiotherapy in pancreatic cancer.

Background and purpose : A method of using electronic portal imaging to design compensators for tangential breast irradiation has been developed. We describe how this has been implemented. Materials and methods : The compensator design method generates wedged and unwedged beam weights, in conjunction with templates for multiple lead-sheet compensators and pseudo-CT outlines. The latter describe the breast and lung profiles in a set of transverse slices. The layers of the compensator and pseudo-CT outlines are transferred to a treatment planning system for verification. The accuracy of the planning system for the high transmission blocks used to describe the compensators has been verified using a plotting tank system. Dose volume histogram data and transaxial and sagittal plan slices have been compared for both standard and compensated treatments for a sample set of five patients. Results : The planning system predicted the dose at depths of 1.5 and 5 cm to within 2% for the compensators tested. The biggest source of discrepancy was a consequence of the planning system requiring blocks to have integer percentage transmission. For all patients studied, the compensated treatment resulted in a significant reduction in the percentage volume outside the 95–105% dose, with an average reduction of 10.2%. The percentage volume outside the 95–107% dose was also reduced by typically 3.4%. The implementation was found to yield a convenient automatic method of designing compensators using electronic portal imaging and verifying the results using a planning system. Conclusions : These results indicate that this method of implementation can be used in practice. The dosimetric accuracy of the treatment planning system is limited by the requirement that blocks should be of integer transmission, but this effect is small.

Aims The α/β ratio for prostate cancer is thought to be low and less than for the rectum, which is usually the dose-limiting organ. Hypofractionated radiotherapy should therefore improve the therapeutic ratio, increasing cure rates with less toxicity. A number of models for predicting biochemical relapse-free survival have been developed from large series of patients treated with conventional and moderately hypofractionated radiotherapy. The purpose of this study was to test these models when significant numbers of patients treated with profoundly hypofractionated radiotherapy were included. Materials and methods A systematic review of the literature with regard to hypofractionated radiotherapy for prostate cancer was conducted, focussing on data recently presented on prostate stereotactic body radiotherapy. For the work described here, we have taken published biochemical control rates for a range of moderately and profoundly fractionated schedules and plotted these together with a range of radiobiological models, which are described. Results The data reviewed show consistency between the various radiobiological model predictions and the currently observed data. Conclusion Current radiobiological models provide accurate predictions of biochemical relapse-free survival, even when profoundly hypofractionated patients are included in the analysis.

In proton therapy, a radiobiological effectiveness ratio (RBE) of 1.1 (RBE1.1) is often used. In reality, RBE depends on dose, linear energy transfer (LET), biological end point, and tissue type. Using a value of RBE that may be not accurate may affect dose calculation and hence, outcome.

Purpose Most studies investigating the dose–response of the rectum focus on rectal bleeding. However, it has been reported that other symptoms such as urgency or sphincter control have a large impact on quality-of-life and that different symptoms are related to the dose to different parts of the anorectal wall. In this study correlations between the 3D dose distribution to the anal-sphincter region and radiation-induced side-effects were quantified. Materials and methods Dose–surface maps of the anal canal were generated. Next, longitudinal and lateral extent and eccentricity were calculated at different dose levels; DSHs and DVHs were also determined. Correlations between these dosimetric measures and seven clinically relevant endpoints were determined by assessing dosimetric constraints. Furthermore, an LKB model was generated. The study was performed using the data of 388 prostate patients from the RT01 trial (ISRCTN 47772397). Results Subjective sphincter control was significantly correlated with the dose to the anal surface. The strongest correlations were found for lateral extent at 53Gy ( p =0.01). Outcome was also significantly correlated with the DSH and the mean dose to the anal surface. Conclusions The dose to the anal sphincter region should be taken into account when generating treatment-plans. This could be done using shape-based tools, DSH/DVH-based tools or an NTCP model.

BACKGROUND: When induction chemotherapy (IC) is used prior to chemoradiotherapy (CRT) in head and neck cancer (HNC), functional imaging (FI) may inform adaptation of treatment plans with the aim of optimising outcomes. Understanding the impact of IC on FI parameters is, therefore, essential. PURPOSE: To prospectively evaluate the feasibility of acquiring serial FI ((18)F-FDG-PET, diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI) and its role in defining individualised treatment regimens following IC in HNC. METHODS AND MATERIALS: Ten patients with stage III and IV HNC underwent conventional (CT and MRI) and functional (DW, DCE-MRI and (18)F-FDG-PET/CT) imaging at baseline and following two cycles of IC prior to definitive CRT. RESULTS: One patient withdrew due to claustrophobia. Seven out of nine patients had a complete metabolic response to IC on (18)F-FDG-PET imaging. DCE-MRI showed a significant fall in transfer constant (K(trans)) (0.209 vs 0.129 min(-1)P

Background and purpose The Normal Tissue Complication Probability (NTCP) for rectum is usually defined for late rectal bleeding. This study calculates NTCP parameter values for additional rectal toxicity endpoints observed in clinical practise. Materials and methods 388 patients from the multicentre MRC-RT01 prostate conformal radiotherapy trial (ISRCTN 47772397) were used to derive independent Lyman Kutcher Burman model (LKB) parameters for five late rectal toxicity endpoints: rectal bleeding, proctitis, stool frequency, loose stools and rectal urgency. The parameters were derived using maximum likelihood estimation. Bootstrap and leave-one-out methods were employed to test the generalisability of the results for use in a general population. Results A consistent pattern of increasing value of TD50(1) for Grade 2 toxicity only compared to Grades 1 and 2 toxicity was observed for all endpoints. Parameter values varied between endpoints (particularly for the volume parameter n). TD50(1), m and n were 68.5 Gy (95% CI)(66.8–70.8), 0.15 (0.13–0.17) and 0.13 (0.10–0.17), respectively, for G2 rectal bleeding. Bootstrap and leave-one-out results showed that the rectal bleeding and proctitis parameter fits were extremely robust. Conclusions The variation between the values derived for different endpoints may indicate different patho-physiological responses of the rectum to radiation. Therefore different parameter sets would be required to predict specific rectal toxicity endpoints.

Radiotherapy forms one of the major treatment modalities for head and neck cancers (HNC), and precision radiotherapy techniques, such as intensity-modulated radiotherapy require accurate target delineation to ensure success of the treatment. Conventionally used imaging modalities, such as X-ray computed tomography (CT) and magnetic resonance imaging are used to delineate the tumor. Imaging, such as positron emission tomography (PET)-CT, which combines the functional and anatomic modalities, is increasingly being used in the management of HNC. Currently, 18-fluorodeoxyglucose is the most commonly used radioisotope, which is accumulated in areas of high glucose uptake, such as the tumor tissue. Because most disease recurrences are within the high-dose radiotherapy volume, defining a biological target volume for radiotherapy boost is an attractive approach to improve the results. There are many challenges in employing the PET-CT for radiotherapy planning, such as patient positioning, target edge definition, and use of new PET tracers, which represent various functional properties, such as hypoxia, protein synthesis, and proliferation. The role of PET-CT for radiotherapy planning is ever expanding and more clinical data underlining the advantages and challenges in this approach are emerging. In this article, we review the current clinical evidence for the application of functional imaging to radiotherapy planning and discuss some of the current challenges and possible solutions that have been suggested to date.

PURPOSE: Radical radiotherapy for prostate cancer is effective but dose limited because of the proximity of normal tissues. Comprehensive dose-volume analysis of the incidence of clinically relevant late rectal toxicities could indicate how the dose to the rectum should be constrained. Previous emphasis has been on constraining the mid-to-high dose range (>/=50 Gy). Evidence is emerging that lower doses could also be important. METHODS AND MATERIALS: Data from a large multicenter randomized trial were used to investigate the correlation between seven clinically relevant rectal toxicity endpoints (including patient- and clinician-reported outcomes) and an absolute 5% increase in the volume of rectum receiving the specified doses. The results were quantified using odds ratios. Rectal dose-volume constraints were applied retrospectively to investigate the association of constraints with the incidence of late rectal toxicity. RESULTS: A statistically significant dose-volume response was observed for six of the seven endpoints for at least one of the dose levels tested in the range of 30-70 Gy. Statistically significant reductions in the incidence of these late rectal toxicities were observed for the group of patients whose treatment plans met specific proposed dose-volume constraints. The incidence of moderate/severe toxicity (any endpoint) decreased incrementally for patients whose treatment plans met increasing numbers of dose-volume constraints from the set of V30

Background and purpose Accurate reporting of complications following radiotherapy is an important part of the feedback loop to improve radiotherapy techniques. The definition of toxicity is normally regarded as the maximum or peak (P) grade of toxicity reported over the follow-up period. An alternative definition (integrated longitudinal toxicity (ILT)) is proposed which takes into account both the severity and the duration of the complication. Methods and materials In this work, both definitions of toxicity were used to derive dose–volume constraints for six specific endpoints of late rectal toxicity from a cohort of patients who received prostate radiotherapy in the MRC RT01 trial. The dose–volume constraints were derived using ROC analysis for 30, 40, 50, 60, 65 and 70 Gy. Results Statistically significant dose–volume constraints were not derived for all dose levels tested for each endpoint and toxicity definition. However, where both definitions produced constraints, there was generally good agreement. Variation in the derived dose–volume constraints was observed to be larger between endpoints than between the two definitions of toxicity. For one endpoint (stool frequency (LENT/SOM)) statistically significant dose–volume constraints were only derived using ILT. Conclusions The longitudinal definition of toxicity (ILT) produced results consistent with those derived using peak toxicity and in some cases provided additional information which was not seen by analysing peak toxicity alone.

INTRODUCTION: The prognosis from non-small cell lung cancer remains poor, even in those patients suitable for radical radiotherapy. The ability of radiotherapy to achieve local control is hampered by the sensitivity of normal structures to irradiation at the high tumour doses needed. This study aimed to look at the potential gain in tumour control probability from dose escalation facilitated by moderate deep inspiration breath-hold. METHOD: The data from 28 patients, recruited into two separate studies were used. These patients underwent planning with and without the use of moderate deep inspiration breath-hold with an active breathing control (ABC) device. Whilst maintaining the mean lung dose (MLD) at the level of the conventional plan, the ABC plan dose was theoretically escalated to a maximum of 84 Gy, constrained by usual normal tissue tolerances. Calculations were performed using data for both lungs and for the ipsilateral lung only. Resulting local progression-free survival at 30 months was calculated using a standard logistic model. RESULTS: The prescription dose could be escalated from 64 Gy to a mean of 73.7+/-6.5 Gy without margin reduction, which represents a statistically significant increase in tumour control probability from 0.15+/-0.01 to 0.29+/-0.11 (p

BACKGROUND AND PURPOSE: As techniques for radiotherapy delivery have developed, increasingly accurate localisation of disease is demanded. Functional imaging, particularly PET and its fusion with anatomical modalities, such as PET/CT, promises to improve detection and characterisation of disease. This study evaluated the impact of (18)FDG-PET/CT on radiotherapy target volume definition in head and neck cancer (HNC). MATERIALS AND METHODS: The PET/CT scans of patients with HNC were used in a radiotherapy planning (RTP) study. The gross tumour volume (GTV), clinical target volume (CTV) and planning target volume (PTV) were defined conventionally and compared to those defined using the PET/CT. Data were reported as the median value with 95% confidence intervals. RESULTS: Eighteen patients were consented, 9 had known primary tumour site, 9 presented as unknown primary. In nine cases where the primary site was known, the combined primary and nodal GTV (GTVp+n) increased by a median of 6.1cm(3) (2.6, 12.2) or 78% (18, 313), p=0.008 with CTV increasing by a median of 10.1cm(3) (1.3, 30.6) or 4% (0, 13) p=0.012. In 9 cases of unknown primary the GTVp+n increased by a median 6.3 cm(3) (0.2, 15.7) or 61% (4, 210), p=0.012, with CTV increasing by a median 155.4 cm(3) (2.7, 281.7) or 95% (1, 137), p=0.008. CONCLUSION: (18)FDG-PET revealed disease lying outside the conventional target volume, either extending a known area or highlighting a previously unknown area of disease, including the primary tumour in 5 cases. We recommend PET/CT in the RTP of all cases of unknown primary. In patients with a known primary, although the change in volume was statistically significant the clinical impact is less clear. (18)FDG-PET can also show areas within the conventional target volume that are hypermetabolic which may be possible biological target volumes for dose escalation studies in the future.

Dosimetry for targeted radionuclide therapy is necessary for treatment planning and radiation protection. Currently, there are no standard methods either for performing dosimetry or to evaluate the uncertainties inherent in the dosimetric calculations. In this paper, we present an experimental method using polymer gel dosimeters, whereby absorbed-dose distributions resulting from nonuniform distributions of activity may be determined directly from T(2) magnetic resonance imaging (MRI) as well as from scintigraphic images. A phantom containing a nonuniform distribution of I-131 was prepared by mixing 58 MBq of activity within the gel as it was solidifying. The resulting absorbed-dose distribution was determined directly from the MRI and from sequential single-photon emission computed tomography (SPECT) images using the Medical Internal Radiation Dose (MIRD) schema. The MRI data were quantified using 12 calibration vials uniformly irradiated by 0-12 MBq of I-131. The agreement between the two absorbed-dose maps was verified by convolving the MRI-based absorbed-dose map with the SPECT system point spread function, which gave a correlation coefficient of 0.96. It was seen that the absorbed-dose distribution, as imaged by the MRI, was misrepresented by the SPECT owing to its relatively poor spatial resolution, which included a shift of the voxel containing the maximum absorbed dose. This technique could provide an independent benchmark for assessing patient-specific dosimetry and, therefore, could be used as a basis for quality control for dosimetry.

This paper describes the development of a protocol for SPECT-based tumor dosimetry for (131)I-mIBG therapy patients with high-risk neuroblastoma. The treatment aims to deliver a whole-body dose of 4 Gy in two fractions. Whole-body retention measurements taken during the first fraction are used to guide the second therapy administration. The tumor dose from 3 patients was assessed by acquiring a minimum of three SPECT scans. Dead-time and triple-energy window scatter corrections were applied. The images were reconstructed using filtered backprojection with a Chang attenuation correction, and a phantom-based calibration factor was used to convert to activity. A monoexponential fit was made to the data, and instantaneous uptake was assumed. Tumor absorbed-dose ratios were used to analyze intrapatient variations, and absolute tumor dosimetry was used to assess interpatient variation. The whole-body dose administered ranged from (3.7 +/- 0.1) Gy to (3.9 +/- 0.3) Gy. This method is more accurate than a weight-based administration method. Despite this, a variation in absorbed tumor dose of 10-103 Gy was observed. All repeat doses were in the same order of magnitude, although 2 patients received a lower tumor dose per MBq from the second therapy owing to a shorter biological half-life. The tumor dosimetry protocol was simple to apply and reproducible, but the errors in image quantitation needed to be evaluated.

The additional benefit of positron emission tomography (PET) in the initial staging of non-small cell lung cancer (NSCLC) has generated interest in 18 F-fluorodeoxyglucose (FDG) PET as a means of defining the extent of primary lung tumour for radiotherapy treatment planning (RTP). A review of published data suggests that PET results in a reduction in the CT-derived GTV for NSCLC primary target volume in 15% of the patients. This is principally due to the ability of PET to distinguish tumour from atelectasis. However, the difficulty of tumour edge definition, limited spatial resolution and tumour motion during image acquisition currently limits the accuracy of PET in target volume delineation in NSCLC without adjacent lung consolidation. This is compounded by the lack of data correlating PET with spatial pathology at the primary tumour site. With the current technical limitations, it is not established that PET can add accuracy to the CT-defined primary target delineation in RTP of NSCLC. It is hoped that advances in PET and combined PET/CT imaging may overcome some of the technical limitations. Future use of PET for primary tumour delineation in NSCLC will also be critically dependent on the detailed studies of imaging–pathology correlation.