F. McDonald

Introduction of a Quality Management System and Outcome After Hematopoietic Stem-Cell Transplantation

PURPOSE A comprehensive quality management system called JACIE (Joint Accreditation Committee International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation), was introduced to improve quality of care in hematopoietic stem-cell transplantation (HSCT). We therefore tested the hypothesis that the introduction of JACIE improved patient survival. PATIENTS AND METHODS Data on 41,623 allogeneic (39%) and 66,281 autologous (61%) HSCTs for an acquired hematologic disorder performed between 1999 and 2007 by 421 teams in Europe were used to assess the outcomes of patients who received a transplantation at baseline (> 3 years before application or no application), during preparation (3 years before application), during application (time from application to accreditation), and after JACIE accreditation. The analysis was clustered by team and stratified for year of HSCT, donor type, disease, conditioning, and gross national income per capita of the respective country. Patients risks were adjusted for by their European Group for Blood and Marrow Transplantation score. RESULTS Patient outcome was systematically better when the transplantation center was at a more advanced phase of JACIE accreditation, independent of year of transplantation and other risk factors. Improvement was robust as quantified for relapse-free survival after allogeneic HSCT compared with baseline by a hazard ratio (HR) of 0.96 (95% CI, 0.90 to 1.03; P = .22) for preparation, 0.95 (95% CI, 0.88 to 1.03; P = .20) for application, and 0.86 (95% CI, 0.78 to 0.95; P = .01) for the accreditation (test for trend P = .01). Improvement from baseline was similar after autologous HSCT (HR for accreditation, 0.83; 95% CI, 0.74 to 0.93; P < .01). CONCLUSION Even with all the limitations of an observational study, these findings support the hypothesis that introduction of a comprehensive clinical quality management system is associated with improved outcome of patients after HSCT.

Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial

Summary Background The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. Methods We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. Findings Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19–1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. Interpretation Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. Funding Research for Patient Benefit Programme from the UK National Institute for Health Research.

Clinical development of new drug-radiotherapy combinations

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Groups consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.

Lung stereotactic body radiotherapy with an MR-linac – Quantifying the impact of the magnetic field and real-time tumor tracking

Background and purpose There are concerns that radiotherapy doses delivered in a magnetic field might be distorted due to the Lorentz force deflecting secondary electrons. This study investigates this effect on lung stereotactic body radiotherapy (SBRT) treatments, conducted either with or without multileaf collimator (MLC) tumor tracking. Material and methods Lung SBRT treatments with an MR-linac were simulated for nine patients. Two different treatment techniques were compared: conventional, non-tracked deliveries and deliveries with real-time MLC tumor tracking, each conducted either with or without a 1.5 T magnetic field. Results Slight dose distortions at air-tissue-interfaces were observed in the presence of the magnetic field. Most prominently, the dose to 2% of the skin increased by 1.4 Gy on average. Regardless of the presence of the magnetic field, MLC tracking was able to spare healthy tissue, for example by decreasing the mean lung dose by 0.3 Gy on average, while maintaining the target dose. Conclusions Accounting for the magnetic field during treatment plan optimization allowed for design and delivery of clinically acceptable lung SBRT treatments with an MR-linac. Furthermore, the ability of MLC tumor tracking to decrease dose exposure of healthy tissue, was not inhibited by the magnetic field.

Effect of MLC tracking latency on conformal volumetric modulated arc therapy (VMAT) plans in 4D stereotactic lung treatment

Background and purpose The latency of a multileaf collimator (MLC) tracking system used to overcome respiratory motion causes misalignment of the treatment beam with respect to the gross tumour volume, which may result in reduced target coverage. This study investigates the magnitude of this effect. Material and methods Simulated superior–inferior breathing motion was used to construct histograms of isocentre offset with respect to the gross tumour volume (GTV) for a variety of tracking latencies. Dose distributions for conformal volumetric modulated arc therapy (VMAT) arcs were then calculated at a range of offsets and summed according to these displacement histograms. The results were verified by delivering the plans to a Delta4 phantom on a motion platform. Results In the absence of an internal target margin, a tracking latency of 150 ms reduces the GTV D95% by approximately 2%. With a margin of 2 mm, the same drop in dose occurs for a tracking latency of 450 ms. Lung V13Gy is unaffected by a range of latencies. These results are supported by the phantom measurements. Conclusions Assuming that internal motion can be modelled by a rigid translation of the patient, MLC tracking of conformal VMAT can be effectively accomplished in the absence of an internal target margin for substantial breathing motion (4 s period and 20 mm peak–peak amplitude) so long as the system latency is less than 150 ms.

UK Consensus on Normal Tissue Dose Constraints for Stereotactic Radiotherapy

Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally.

Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study

Introduction The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of ‘isotoxic’ radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable. Methods and analysis Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years. Ethics and dissemination The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West—Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally. Trial registration number NCT01836692; Pre-results.

First MRI application of an active breathing coordinator

Abstract A commercial active breathing coordinator (ABC) device, employed to hold respiration at a specific level for a predefined duration, was successfully adapted for magnetic resonance imaging (MRI) use for the first time. Potential effects of the necessary modifications were assessed and taken into account. Automatic MR acquisition during ABC breath holding was achieved. The feasibility of MR-ABC thoracic and abdominal examinations together with the advantages of imaging in repeated ABC-controlled breath holds were demonstrated on healthy volunteers. Five lung cancer patients were imaged under MR-ABC, visually confirming the very good intra-session reproducibility of organ position in images acquired with the same patient positioning as used for computed tomography (CT). Using identical ABC settings, good MR-CT inter-modality registration was achieved. This demonstrates the value of ABC, since application of T1, T2 and diffusion weighted MR sequences provides a wider range of contrast mechanisms and additional diagnostic information compared to CT, thus improving radiotherapy treatment planning and assessment.

Defining bowel dose volume constraints for bladder radiotherapy treatment planning

AIMS Increases to radiotherapy dose are constrained by normal tissue effects. The relationship between bowel dose volume data and late bowel toxicity in patients with muscle-invasive bladder cancer treated with radical radiotherapy was assessed. MATERIALS AND METHODS The bowel was contoured retrospectively on radiotherapy plans of 47 patients recruited to the BC2001 trial (CRUK/01/004). The relationship between bowel volume at various dose levels and prospectively collected late bowel toxicity was explored. RESULTS Fifteen per cent and 6% of patients experienced grade 1 and grade 2 or more late bowel toxicity, respectively. The mean bowel volume was significantly less at doses ≥50 Gy in those treated with reduced high dose volume radiotherapy compared with standard radiotherapy. The probability of late bowel toxicity increased as bowel volume increased (P ≤ 0.05 for dose levels 30-50 Gy). No grade 2 or more late bowel toxicity was observed in patients with bowel volumes under the thresholds given in the model that predict for 25% probability of late bowel toxicity. CONCLUSIONS There is a dose volume effect for late bowel toxicity in radical bladder radiotherapy. We have modelled the probability of late bowel toxicity from absolute bowel volumes to guide clinicians in assessing radical bladder radiotherapy plans. Thresholds predicting for a 25% probability of late bowel toxicity are proposed as dose volume constraints.

ESTRO ACROP guidelines for target volume definition in the treatment of locally advanced non-small cell lung cancer

Radiotherapy (RT) plays a major role in the curative treatment of locally advanced non-small cell lung cancer (NSCLC). Therefore, the ACROP committee was asked by the ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)radiotherapy (RT) and adjuvant RT for locally advanced NSCLC. The guidelines given here are a result of the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing procedure within the committee. Hence, we provide advice for methods and time-points of diagnostics and imaging before the start of treatment planning and for the mandatory and optional imaging to be used for planning itself. Concerning target volumes, recommendations are given for GTV delineation of primary tumour and lymph nodes followed by issues related to the delineation of CTVs for definitive and adjuvant radiotherapy. In the context of PTV delineation, recommendations about the management of geometric uncertainties and target motion are given. We further provide our opinions on normal tissue delineation and organisational and responsibility questions in the process of target volume delineation. This guideline intends to contribute to the standardisation and optimisation of the process of RT treatment planning for clinical practice and prospective studies.