• R-CHOP in primary mediastinal B-Cell lymphoma (PMBL): results from the UK NCRI R-CHOP 14 v 21 trial.

      Gleeson, M; Hawkes, E; Cunningham, D; Chadwick, N; Counsell, N; Lawrie, A; Jack, A; Smith, P; Mouncey, P; Pocock, C; et al. (2015)
    • R-GEM-Lenalidomide versus R-GEM-P as second-line treatment of diffuse large B-cell lymphoma: results of the UK NRCI phase II randomised LEGEND trial

      Kuhnl, A; Peckitt, C; Patel, B; Ardeshna, KM; Macheta, MP; Radford, John A; Rod, J; Paneesha, S; Barton, S; Chau, I; et al. (2019)
      Outcome of patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) remains poor, highlighting the need for novel treatment approaches. The multicentre randomised phase II LEGEND trial evaluated lenalidomide in combination with rituximab, methylprednisolone and gemcitabine (R-GEM-L) vs. standard R-GEM-P as second-line treatment of DLBCL. The study closed early to recruitment after the planned interim analysis failed to demonstrate a complete response (CR) rate of ³ 40% in either arm. Among 34 evaluable patients, 7/18 (38.9%) achieved CR with R-GEM-L and 3/16 (18.8%) with R-GEM-P. Median event-free and overall survival was 3.5/3.8 months and 10.8/8.3 months for R-GEM-L and R-GEM-P, respectively. The incidence of grade ³ 3 toxicities was 52% in R-GEM-L and 83% in R-GEM-P. Efficacy and tolerability of R-GEM-L seem comparable with R-GEM-P and other standard salvage therapies, but a stringent design led to early trial closure. Combination of lenalidomide with gemcitabine-based regimens should be further evaluated in r/r DLBCL.
    • R-IDEAL: a framework for systematic clinical evaluation of technical innovations in radiation oncology.

      Verkooijen, H; Kerkmeijer, L; Fuller, C; Huddart, R; Faivre-Finn, Corinne; Verheij, M; Mook, S; Sahgal, A; Hall, E; Schultz, C; et al. (2017)
      The pace of innovation in radiation oncology is high and the window of opportunity for evaluation narrow. Financial incentives, industry pressure, and patients' demand for high-tech treatments have led to widespread implementation of innovations before, or even without, robust evidence of improved outcomes has been generated. The standard phase I-IV framework for drug evaluation is not the most efficient and desirable framework for assessment of technological innovations. In order to provide a standard assessment methodology for clinical evaluation of innovations in radiotherapy, we adapted the surgical IDEAL framework to fit the radiation oncology setting. Like surgery, clinical evaluation of innovations in radiation oncology is complicated by continuous technical development, team and operator dependence, and differences in quality control. Contrary to surgery, radiotherapy innovations may be used in various ways, e.g., at different tumor sites and with different aims, such as radiation volume reduction and dose escalation. Also, the effect of radiation treatment can be modeled, allowing better prediction of potential benefits and improved patient selection. Key distinctive features of R-IDEAL include the important role of predicate and modeling studies (Stage 0), randomization at an early stage in the development of the technology, and long-term follow-up for late toxicity. We implemented R-IDEAL for clinical evaluation of a recent innovation in radiation oncology, the MRI-guided linear accelerator (MR-Linac). MR-Linac combines a radiotherapy linear accelerator with a 1.5-T MRI, aiming for improved targeting, dose escalation, and margin reduction, and is expected to increase the use of hypofractionation, improve tumor control, leading to higher cure rates and less toxicity. An international consortium, with participants from seven large cancer institutes from Europe and North America, has adopted the R-IDEAL framework to work toward coordinated, evidence-based introduction of the MR-Linac. R-IDEAL holds the promise for timely, evidence-based introduction of radiotherapy innovations with proven superior effectiveness, while preventing unnecessary exposure of patients to potentially harmful interventions.
    • R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study.

      Pappo, A; Patel, S; Crowley, J; Reinke, D; Kuenkele, K; Chawla, S; Toner, G; Maki, R; Meyers, P; Chugh, R; et al. (2011-12-01)
      The type 1 insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the pathogenesis of the Ewing sarcoma family of tumors (ESFT). We conducted a multicenter phase II study of the fully human IGF-1R monoclonal antibody R1507 in patients with recurrent or refractory ESFT.
    • Radial artery access for hepatic chemosaturation: the first description of technical feasibility

      Frost, Joshua | Najran, Pavan; Bell, Jon; Mullan, Damian; Radiology and Interventional Radiology, The Christie NHS Foundation Trust, Manchester (2021)
      Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System, Delcath Systems Inc, Wilmington, Delaware) is an interventional radiology procedure that delivers high doses of melphalan, a chemotherapeutic agent, directly to the liver in patients with unresectable primary and secondary liver tumours. Traditionally, CS-PHP is delivered by arterial access via the femoral artery. However, there can be many risks and adverse effects associated with femoral artery punctures, such as retroperitoneal haemorrhage and haematoma formation. The monitoring and bed rest required following the removal of a femoral arterial catheter may also cause significant distress to patients as they remain immobile, potentially prolonging their stay in hospital. The radial artery is an alternative access point, with fewer reported adverse events and increased patient tolerance when compared with femoral access. This case report details the first reported use of Hepatic CHEMOSAT® therapy being delivered via the radial artery. Two patients received hepatic chemosaturation with no reported complications. This report demonstrates that access via the radial artery is a feasible alternative for the delivery of chemotherapy, which may reduce morbidity and the risks usually associated with femoral access.
    • Radial Data Mining to Identify Density-Dose Interactions That Predict Distant Failure Following SABR

      Davey, A.; van Herk, M.; Faivre-Finn, C.; McWilliam, A. (2022)
      Purpose: Lower dose outside the planned treatment area in lung stereotactic radiotherapy has been linked to increased risk of distant metastasis (DM) possibly due to underdosage of microscopic disease (MDE). Independently, tumour density on pretreatment computed tomography (CT) has been linked to risk of MDE. No studies have investigated the interaction between imaging biomarkers and incidental dose. The interaction would showcase whether the impact of dose on outcome is dependent on imaging and, hence, if imaging could inform which patients require dose escalation outside the gross tumour volume (GTV). We propose an image-based data mining methodology to investigate density–dose interactions radially from the GTV to predict DM with no a priori assumption on location. Methods: Dose and density were quantified in 1-mm annuli around the GTV for 199 patients with early-stage lung cancer treated with 60 Gy in 5 fractions. Each annulus was summarised by three density and three dose parameters. For parameter combinations, Cox regressions were performed including a dose–density interaction in independent annuli. Heatmaps were created that described improvement in DM prediction due to the interaction. Regions of significant improvement were identified and studied in overall outcome models. Results: Dose–density interactions were identified that significantly improved prediction for over 50% of bootstrap resamples. Dose and density parameters were not significant when the interaction was omitted. Tumour density variance and high peritumour density were associated with DM for patients with more cold spots (less than 30-Gy EQD2) and non-uniform dose about 3 cm outside of the GTV. Associations identified were independent of the mean GTV dose. Conclusions: Patients with high tumour variance and peritumour density have increased risk of DM if there is a low and non-uniform dose outside the GTV. The dose regions are independent of tumour dose, suggesting that incidental dose may play an important role in controlling occult disease. Understanding such interactions is key to identifying patients who will benefit from dose-escalation. The methodology presented allowed spatial dose–density interactions to be studied at the exploratory stage for the first time. This could accelerate the clinical implementation of imaging biomarkers by demonstrating the impact of incidental dose for tumours of varying characteristics in routine data.
    • RADIANT-4: Efficacy and safety of everolimus in advanced, nonfunctional neuroendocrine tumors (NET) of the lung or gastrointestinal (GI) tract

      Yao, J; Singh, S; Wolin, E; Voi, M; Pacaud, L; Lincy, J; Sachs, C; Valle, Juan W; Van Cutsem, E; Shimada, Y; et al. (2015)
    • Radiation and hypothalamic-pituitary function.

      Littley, M D; Shalet, Stephen M; Beardwell, Colin G (1990-03)
      In adults, hypopituitarism is a common consequence of external radiotherapy. The clinical manifestations may be subtle and develop insidiously many years after radiotherapy. Anterior pituitary deficiencies can therefore only be detected by regular testing, including dynamic tests of GH and ACTH reserve. Although the deficiencies most commonly develop in the order GH, gonadotrophins, ACTH then TSH, this sequence may not be predictable in an individual patient and comprehensive testing is therefore required. The tests should ideally be performed annually for at least 10 years after treatment or until deficiency has been detected and treated. It is not only the patients with pituitary disease who are at risk of developing hypopituitarism after radiotherapy. Any patient who receives a total dose of irradiation of 20 Gy or more to the hypothalamic-pituitary axis is at risk of hypopituitarism, although the threshold dose may be lower than this. This is particularly important in the long-term survivors of malignant disease in whom endocrine morbidity may be relatively common and in whom this can be easily treated, with consequent improvement in quality of life. Whilst patients who receive a high total dose of irradiation are at increased risk of developing multiple deficiencies, a higher fraction size also increases the risk of anterior pituitary failure. There is good evidence that the earliest damage to the hypothalamic-pituitary axis after external radiotherapy is at the level of the hypothalamus. However, patients who undergo pituitary ablation with interstitial radiotherapy or heavy particle beams are likely to sustain direct damage to the pituitary. In these patients, the sequence in which individual pituitary hormone deficiencies develop is generally the same as that observed with the hypothalamic damage after conventional external radiotherapy. The increasing use of radiotherapy as a means of treatment for malignant disease means that new groups of patients with potential for endocrine dysfunction are emerging. Whole body irradiation in the preparation for bone marrow transplant is one such treatment and although hypothalamic-pituitary damage appears to be confined to GH deficiency in children, longitudinal experience is limited to date, particularly in adults. The treatment of malignant disease in childhood is of particular importance in terms of the delayed endocrine sequelae. The hypothalamic-pituitary axis may not be the only endocrine tissue damaged by treatment in these patients and management is therefore more complicated. In the growing child, the potential association of growth hormone deficiency, gonadal failure or premature puberty and thyroid dysfunction mean that expert endocrine supervision is essential for optimum long-term outcome.
    • Radiation and neuroregulatory control of growth hormone secretion.

      Ogilvy-Stuart, Amanda L; Wallace, W Hamish B; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, UK. (1994-08)
      OBJECTIVE: Cranial irradiation frequently results in growth hormone (GH) deficiency. Patients with radiation-induced GH deficiency usually remain responsive to exogenous growth hormone releasing hormone, implying radiation damages the hypothalamus rather than the pituitary. Little is known about the effect of cranial irradiation on the neuroendocrine control of GH secretion. This study was to determine the effect of cranial irradiation on somatostatin tone. DESIGN: Somatostatin tone was examined by manipulating cholinergic tone in young adults with radiation-induced GH deficiency and a control population. Each individual underwent three separate studies: the GH response to 100 micrograms GHRH-(1-29)-NH2 was assessed alone, and 60 minutes after pyridostigmine or pirenzepine. PATIENTS: Eight young male adults with radiation induced GH deficiency following treatment in childhood for a brain tumour or acute lymphoblastic leukaemia, and ten healthy adult men were studied. MEASUREMENTS: Serum growth hormone was measured at 15-minute intervals throughout each of the three study periods. RESULTS: One of 10 controls and four of eight irradiated subjects had a peak GH level to GHRH analogue of less than 20 mU/l. After pretreatment with pyridostigmine, all subjects except one irradiated subject had a peak GH level of greater than 20 mU/l. Pretreatment with pyridostigmine and pirenzepine significantly modified the GH response to GHRH analogue within both groups (P < 0.0005). Pretreatment with pyridostigmine significantly enhanced the GH response to GHRH analogue (median (range) area under the curve, 9029 (1956-20940) mU/l/min in controls vs 1970 (628-3608) mU/l/min in the irradiated group) compared with GHRH analogue alone (1953 (512-16140) mU/l/min in control group vs 997 (266-3488) mU/l/min in the irradiated group). Pretreatment with pirenzepine significantly attenuated the GH response to GHRH analogue (552 (64-1274) mU/l/min in controls vs 305 (134-2726) mU/l/min in irradiated group). Between the groups there was no significant difference in GH area under the curve (AUC) after GHRH analogue alone. There was a significantly (P = 0.0014) greater increment of GH secretion after pyridostigmine and GHRH analogue compared with GHRH analogue alone (difference in AUC of pyridostigmine+GHRH analogue and GHRH analogue alone 6348 (696-12856) mU/l controls vs 542 (120-1340) mU/l in the irradiated group) and significantly (P = 0.033) greater suppression of GH secretion after pirenzepine and GHRH analogue compared with GHRH analogue alone (difference in AUC of GHRH analogue alone and pirenzepine+GHRH analogue 1644 (222-15205) mU/l in controls vs 479 (469-1623) mU/l in the irradiated group) in the control population compared with those who had received cranial irradiation in childhood. CONCLUSIONS: These data suggest that cranial irradiation reduces but does not abolish somatostatin (SRIH) tone and also reduces endogenous GHRH secretion. Although SRIH tone is reduced, it can be increased by cholinergic manipulation and is therefore not irreversibly fixed. This has possible implications if GHRH analogues were used to treat children with radiation induced GH deficiency.
    • Radiation and pituitary dysfunction.

      Shalet, Stephen M (1993-01-14)
    • Radiation and the genome: from risks to opportunities for therapeutic exploitation.

      Robson, T; West, Catharine M L; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK. T.Robson@qub.ac.uk (2010-08)
      On 1 December 2009, the Radiation and Cancer Biology Committee of the British Institute of Radiology (BIR) held a one-day conference on the theme of radiation and the genome. Talks covered genomic instability (its importance for radiation-induced carcinogenesis and potential for exploitation in the development of novel chemoradiotherapy combinations) and the prospects of exploiting knowledge of the genome to understand how individual genetic variation can impact on a patient's likelihood of developing toxicity following radiotherapy. The meeting also provided an overview of stem cell biology and its relevance for radiotherapy in terms of both tumour (somatic) and normal tissue (germline) sensitivity to radiation. Moreover, the possibility of manipulating stem cells to reduce radiation-induced normal tissue damage was considered.
    • Radiation and women of child bearing potential.

      Bury, B; Hufton, Alan P; Adams, J (1995-04-22)
    • Radiation biology and oncology in the genomic era.

      Kerns, SL; Chuang, KH; Hall, W; Werner, Z; Chen, Y; Ostrer, H; West, Catharine ML; Rosenstein, B; Department of Radiation Oncology, University of Rochester Medical Center , Rochester, NY (2018)
      Radiobiology research is building the foundation for applying genomics in precision radiation oncology. Advances in high-throughput approaches will underpin increased understanding of radiosensitivity and the development of future predictive assays for clinical application. There is an established contribution of genetics as a risk factor for radiotherapy side effects. An individual's radiosensitivity is an inherited polygenic trait with an architecture that includes rare mutations in a few genes that confer large effects and common variants in many genes with small effects. Current thinking is that some will be tissue specific, and future tests will be tailored to the normal tissues at risk. The relationship between normal and tumor cell radiosensitivity is poorly understood. Data are emerging suggesting interplay between germline genetic variation and epigenetic modification with growing evidence that changes in DNA methylation regulate the radiosensitivity of cancer cells and histone acetyltransferase inhibitors have radiosensitizing effects. Changes in histone methylation can also impair DNA damage response signaling and alter radiosensitivity. An important effort to advance radiobiology in the genomic era was establishment of the Radiogenomics Consortium to enable the creation of the large radiotherapy cohorts required to exploit advances in genomics. To address challenges in harmonizing data from multiple cohorts, the consortium established the REQUITE project to collect standardized data and genotyping for ~5,000 patients. The collection of detailed dosimetric data is important to produce validated multivariable models. Continued efforts will identify new genes that impact on radiosensitivity to generate new knowledge on toxicity pathogenesis and tests to incorporate into the clinical decision-making process.
    • Radiation dose and somatic risk from computed tomography.

      Faulkner, K; Moores, B M; Regional Department of Medical Physics and Bioengineering, Christie Hospital, Manchester, England. (1987)
      Lithium fluoride (LiF) thermoluminescent dosimeters (TLD) have been employed to measure the radiation dose distribution within a phantom and the central axis dose in air. Results are presented for seven (four EMI CT1010, one EMI CT5005, one EMI CT7070 and one Siemens DR2) different machines. Organ doses for four different computed tomography (CT) investigations (head, lung, liver and pelvis) have been estimated from previously published tables and the central axis dose in air in 3 CT units. These estimated organ doses were used in turn to deduce the somatic and genetic risks for the four types of CT examination. These calculations indicate that for an 'average' male patient undergoing a CT examination corresponding to the average conditions encountered, the total somatic risks are 3.15 10(-4), 1.98 10(-4), 2.31 10(-4), and 1.38 10(-4) for head, lung, liver and pelvis scans, respectively. The corresponding figures for female patients are 3.39 10(-4), 3.95 10(-4), 2.73 10(-4), and 1.60 10(-4). The risk from head scanning is approximately 250 times that of a dental pantomograph. Somatic and genetic risks will be approximately twice as high for contrast examinations.
    • Radiation dose constraints for organs at risk in neuro-oncology; the European Particle Therapy Network consensus.

      Lambrecht, M; Eekers, D; Alapetite, C; Burnet, N; Calugaru, V; Coremans, I; Fossati, P; Høyer, M; Langendijk, J; Romero, A; et al. (2018-05-17)
      Abstract PURPOSE: For unbiased comparison of different radiation modalities and techniques, consensus on delineation of radiation sensitive organs at risk (OARs) and on their dose constraints is warranted. Following the publication of a digital, online atlas for OAR delineation in neuro-oncology by the same group, we assessed the brain OAR-dose constraints in a follow-up study. METHODS: We performed a comprehensive search to identify the current papers on OAR dose constraints for normofractionated photon and particle therapy in PubMed, Ovid Medline, Cochrane Library, Embase and Web of Science. Moreover, the included articles' reference lists were cross-checked for potential studies that met the inclusion criteria. Consensus was reached among 20 radiation oncology experts in the field of neuro-oncology. RESULTS: For the OARs published in the neuro-oncology literature, we summarized the available literature and recommended dose constraints associated with certain levels of normal tissue complication probability (NTCP) according to the recent ICRU recommendations. For those OARs with lacking or insufficient NTCP data, a proposal for effective and efficient data collection is given. CONCLUSION: The use of the European Particle Therapy Network-consensus OAR dose constraints summarized in this article is recommended for the model-based approach comparing photon and proton beam irradiation as well as for prospective clinical trials including novel radiation techniques and/or modalities.
    • Radiation dose effect in locally advanced non-small cell lung cancer.

      Kong, F M S; Zhao, J; Wang, J; Faivre-Finn, Corinne; Department of radiation oncology, GRU Cancer Center, August, Georgia, USA (2014-04)
      Radiation is the foundation of treatment for locally advanced non-small cell lung cancer (NSCLC), and as such, optimal radiation dose is essential for successful treatment. This article will briefly review biological considerations of radiation dose and their effect in the context of three-dimensional conformal radiation therapy (3D-CRT) including intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) for NSCLC. It will focus on literature review and discussions regarding radiation dose effect in locally advanced NSCLC including potential severe and lethal toxicities of high dose radiation given with concurrent chemotherapy. Potential new approaches for delivering safe and effective doses by individualizing treatment based on functional imaging are being applied in studies such as the PET boost trial and RTOG1106. The RTOG concept of delivering high dose radiation to the more resistant tumors with the use of isotoxic dose prescription and adaptive planning will also be discussed in detail.
    • Radiation dose received by patients during barium meal investigations under automatic brightness control.

      Faulkner, K; Bramall, G; Regional Department of Medical Physics and Bioengineering, Christie Hospital and Holt Radium Institute, Wilmslow Road, Withington, Manchester M20 9BX (1985-01)
      The radiation dose to a group of patients undergoing double-contrast barium meal investigations was monitored using lithium fluoride thermoluminescent dosemeters (TLD). All examinations were performed by the same radiologist in two rooms at the same hospital. Both rooms contained equipment with an undercouch tube/overcouch image intensifier configuration. The examinations were performed at a pre-selected tube potential using automatic brightness control which varied the screening current to keep the dose rate at the image intensifier input surface constant. It may be deduced from the results that there is a significant difference in mean radiation dose between the two rooms. These measurements were used to estimate the radiation dose to other organs, such as the testes, ovaries, uterus and active bone marrow.
    • Radiation dose to heart base linked with poorer survival in lung cancer patients.

      McWilliam, Alan; Kennedy, Jason; Hodgson, C; Vasquez Osorio, E; Faivre-Finn, Corinne; van Herk, Marcel; Division of Molecular and Clinical Cancer Science, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester (2017-11)
      Advances in radiotherapy (RT) have allowed an increased proportion of lung cancer patients to be treated curatively. High doses delivered to critical thoracic organs can result in excess mortality with tolerance doses poorly defined. This work presents a novel method of identifying anatomical dose-sensitive regions within the thorax.
    • Radiation dose to neonates on a Special Care Baby Unit.

      Faulkner, K; Barry, J L; Smalley, P; Regional Department of Medical Physics and Bioengineering, Christie Hospital, Manchester. (1989-03)
      Neonates on a Special Care Baby Unit often require radiography to monitor the progress of their treatment and as a result can have a large number of radiographs taken during their stay in hospital. The skin entrance dose was estimated from a knowledge of the technique factors, X-ray tube output and backscatter factors. Normalized organ dose data were employed to estimate the radiation dose to a number of critical organs. A number of methods of reducing the radiation dose to neonates were investigated. Initially, this involved changing the radiographic technique factors and introducing a lead rubber adjustable collimator, placed on top of the incubator, in addition to the light beam diaphragms on the X-ray tube. It was deduced from the results of calculations that these modifications to the radiographic examination technique had reduced the average entrance dose per radiograph from 92 mu Gy to 58 mu Gy, a reduction of 37%. Later, a rare-earth film-screen combination was introduced to replace the existing fast calcium tungstate screens. This enabled the average entrance dose per radiograph to be reduced to 39 mu Gy, a further reduction of 33%. The mean radiation dose to a neonate is mainly determined by the number of radiographs taken and this is dependent on the clinical symptoms.
    • Radiation dose to patient and staff during percutaneous nephrostolithotomy.

      Rao, P N; Faulkner, K; Sweeney, J K; Asbury, D L; Sambrook, P; Blacklock, N J; Department of Urology, University Hospital of South Manchester. (1987-06)
      The radiation dose to the patient and to members of staff was monitored during 18 procedures for the percutaneous removal of renal stones. It was found that the radiation dose to the patient was minimal and was about the same as for an IVU. The overall dose to the staff was acceptably low and within safety limits. It was concluded that PCNL is a safe procedure from the radiation point of view but it may be advisable to take certain precautions if the workload is high.