• SABR re-irradiation of pelvic cancer recurrences: photon vs proton beam therapy

      Glassborow, E.; Richardson, J.; Clarke, Mathew F; Murray, L.; Speight, R.; Aspin, L.; Gregory, S.; Handley, J; Chuter, Robert; The Christie NHS Foundation Trust, Christie Medical Physics and Engineering, Manchester, (2020)
      Purpose or Objective Patients who experience a pelvic cancer recurrence in or near the region that received initial radiotherapy for the primary disease, typically have few treatment options. OARs have often reached their dose constraint limits leaving standard re-irradiation (reRT) unavailable. Alternatives include surgery, which may be extensive, and chemotherapy, which is typically reserved for wide-spread or symptomatic disease. Despite OAR dose concerns, photon SABR reRT has been utilised with promising initial results but can still struggle to meet constraints. Proton beam therapy (PBT) could offer an improvement through characteristic distal dose fall off. This project aims to establish whether PBT can achieve reduced OAR doses for equal or improved target coverage, compared to photon SABR. Material and Methods PBT plans have been retrospectively created in Eclipse v13.7 on CT data sets for 15 patients treated with photon SABR reRT for pelvic recurrence reRT under NHS England’s Commissioning through Evaluation (CtE) programme between 2016-2017. The photon SABR plans were created in Monaco v5.1, using a VMAT technique and had been prescribed to a 5mm CTV-PTV expansion with an ALARP OAR approach. For the PBT plans a spot scanning technique was used, and plans were created to match the SABR prescription of 30Gy in 5 fractions and the CTV coverage aim of V100% ≥ 95%. An ALARP approach was taken for OAR constraints, aiming to reach an ‘ideal’ constraint obtained by cumulative EQD2 calculations subtracting the primary radiation dose from the CtE constraints. PBT plans were prescribed to the CTV and assessed under uncertainty conditions of ±5mm shifts in all axes, and a nominal ±3.5% stopping power uncertainty. The CTV and OAR dose statistics from the nominal PBT plans were then compared to those from the original clinically delivered photon SABR plans. Results Dosimetric comparison of relevant OAR statistics seen in Figure 1 shows a marked decrease in OAR dose using PBT. Only the small bowel saw any sizeable increase in dose in the PBT plan, seen in only 3 patients. A smaller increase by PBT was seen in the cauda equina, vessels, and colon, for a 4th patient. The largest dose reductions were seen for the sacral plexus, up to 18Gy. Conclusion PBT has the potential to make significant dose reductions for OARS in the pelvic reRT setting. These savings are most pronounced for OARs that abut the target on one side. Less impact is seen when OARs surround the target, as with small bowel. This offers the possibility of increased eligibility within this patient group, to include those who due to OAR doses may have been ineligible for photon SABR, and may even provide room for dose escalation. Whilst this study has made initial steps in the development of the PBT planning technique to align with practical deliverability, further work is required to investigate robustness under inter- and intra-fraction patient variation to determine effective set up and imaging strategies for a PBT technique for this patient group.
    • SABR versus conventional fractionation regimens in NSCLC

      Joseph, N; Choudhury, Ananya; Ministry of Health, Colombo 01000, Sri Lanka. (2019)
    • SABRE 1 (Surgery Against Brachytherapy - a Randomised Evaluation): feasibility randomised controlled trial (RCT) of brachytherapy vs radical prostatectomy in low-intermediate risk clinically localised prostate cancer.

      Eccles, B; Cross, W; Rosario, D; Doble, A; Parker, C; Logue, John P; Little, L; Stanton, L; Bottomley, D; University of Southampton Clinical Trials Unit, Southampton. (2013-08)
      To determine the feasibility of a phase III randomised controlled trial of brachytherapy vs radical prostatectomy (RP) in men with low-intermediate risk localised prostate cancer.
    • SABRTOOTH: a feasibility study of SABR versus surgery in patients with peripheral stage I NSCLC considered to be at higher risk for surgery

      Franks, K; Mcparland, L; Webster, J; Baldwin, D; Sebag-Montefiore, D; Evison, M; Booton, R; Faivre-Finn, Corinne; Naidu, B; Ferguson, J; et al. (2018)
    • SABRTOOTH: A randomised controlled feasibility study of Stereotactic Ablative Radiotherapy (SABR) with surgery in paTients with peripheral stage I nOn-small cell lung cancer (NSCLC) cOnsidered To be at Higher risk of complications from surgical resection

      Franks, K. N.; McParland, L.; Webster, J.; Baldwin, D. R.; Sebag-Montefiore, D.; Evison, M.; Booton, R.; Faivre-Finn, Corinne; Naidu, B.; Ferguson, J.; et al. (2020)
      Objectives: Stereotactic Ablative Radiotherapy (SABR) is a well-established treatment for medically inoperable peripheral stage I non-small cell lung cancer (NSCLC). Previous non-randomised evidence supports SABR as an alternative to surgery, but high quality randomised controlled trial (RCT) evidence is lacking. The SABRTooth study aimed to establish whether a UK phase III RCT was feasible. Design and methods: SABRTooth was a UK multi-centre, randomised controlled feasibility study targeting patients with peripheral stage I NSCLC considered to be at higher-risk of surgical complications. Fifty-four patients were planned to be randomised 1:1 to SABR or surgery. The primary outcome was monthly average recruitment rates. Results: Between July 2015 and January 2017, 318 patients were considered for the study and 205(64.5%) were deemed ineligible. Of 106 assessed as eligible (33.3%), 24 patients (22.6%) were randomised to SABR (n=14) or surgery (n=10). A key theme for non-participation was treatment preference with 43 (41%) preferring non-surgical treatment and 19(18%) preferring surgery. The average monthly recruitment rate was 1.7 patients against a target of 3. Fifteen patients underwent their allocated treatment, 12 SABR, 3 surgery. Conclusions: We conclude that a phase III RCT randomising higher-risk patients between SABR and surgery is not feasible in the National Health Service (NHS). Patients have pre-existing treatment preferences, which was a barrier to recruitment. A significant proportion of patients randomised to the surgical group declined and chose SABR. SABR remains an alternative to surgery and novel study approaches are needed to define which patients benefit from a non-surgical approach.
    • Sacral insufficiency fracture following pelvic radiotherapy in gynaecological malignancies: development of a predictive model

      Mir, R.; Dragan, A. D.; Mistry, H. B.; Tsang, Y. M.; Padhani, A. R.; Hoskin, Peter J; Mount Vernon Cancer Centre, Northwood, UK; National Radiotherapy Trials Quality Assurance (RTTQA) Group, UK. (2020)
      Aims: To investigate the time-to-event and the evolution of sacral insufficiency fractures in gynaecological patients receiving pelvic external beam radiotherapy (EBRT) in relation to dosimetric and imaging parameters across a spectrum of radiotherapy delivery techniques, and to develop a predictive model with a clinical nomogram to identify those at risk of sacral insufficiency fracture. Materials and methods: Patients who received radical or adjuvant pelvic EBRT for gynaecological malignancy between 2014 and 2019 were identified. The data collected were: demographics and clinical details; radiotherapy planning data: dose, fractionation, technique (fixed-field intensity-modulated radiotherapy, adaptive arc, and non-adaptive arc), 60 Gy simultaneous integrated boost. Each plan was examined to determine the sacral dose in 5%/Gy3 increments. Follow-up magnetic resonance scans were reviewed for insufficiency fractures, defined as linear low T1-weighted signal intensity with a high short-T1 inversion recovery (STIR) signal. The site of insufficiency fracture was recreated on the planning computed tomography, the dose to insufficiency fracture contours was recorded and insufficiency fractures were determined as healed with resolution of high STIR signal. Univariable analysis was conducted of the clinical variables. The area under the receiver operator characteristic curve and odds ratio of the risk prediction model with 95% confidence interval are reported with a nomogram for use in clinical practice. Results: 115 patients were identified; the median imaging follow-up was 12 months (2-47). 37.4% developed sacral insufficiency fractures; 93.0% were detected within 12 months of EBRT. At the final radiological follow-up, 83.7% of insufficiency fractures remained active. The radiotherapy delivery technique was not associated with insufficiency fracture after adjusting for patient age (P = 0.115). The location of the 60 Gy simultaneous integrated boost planning target volume did not impact upon the site of insufficiency fracture or the dose received by the insufficiency fracture sites. Age and V40Gy3 are predictors for insufficiency fracture and form the clinical risk model (receiver operator characteristic 0.72). Conclusions: Age and V40Gy3 predict sacral insufficiency fractures; future work should focus on optimising radiotherapy planning with adoption of a bone-sparing planning approach for those patients at high risk of insufficiency fracture.
    • Safe navigation of CARs in a changing landscape

      Davies, Michelle; Dolan, Evelyn; Neeson, Susan M; Blowers, Elaine; Linton, Kim M; Thistlethwaite, Fiona C; The National Institute for Health Research (NIHR) Manchester Clinical Research Facility, The Christie NHS Foundation Trust, Manchester, UK (2018)
    • Safe transfer of pediatric patients from hematopoietic stem cell transplant unit into the pediatric intensive care unit: views of nurses and physicians

      Hutt, D.; Arjona, E. T.; Mekelenkamp, H.; Galimard, J. E.; Kozijn, A.; Schröder, T.; Gjergji, M.; Dalissier, A.; Liptrott, S. J.; Murray, J.; et al. (2022)
      Sufficient communication between hematopoietic stem cell transplantation (HSCT) and pediatric intensive care unit (PICU) teams is pivotal for a successful advanced support in the PICU for HSCT-related complications. We evaluated perceived communication and barriers between both teams with the aim of providing recommendations for improvement. In this cross‐sectional survey, a self‐designed online questionnaire was distributed among ESPNIC and EBMT members. Data were analyzed using descriptive statistics. Over half of HSCT respondents employed a transfer indication protocol and patient assessment tool, but less structured checklist prior to patient transfer. Nearly all PICU respondents perceived this checklist as improvement for communication. Most HSCT and PICU physicians have daily rounds upon patient transfer while this is mostly missing between nursing teams. Half of both HSCT and PICU nurses indicated that HSCT training for PICU nurses could improve communication and patient transfer. Most respondents indicated that structured meetings between HSCT and PICU nurses could improve communication. Overall there is good communication between HSCT and PICU units, although barriers were noted between members of both teams. Based on our findings, we recommend use of a structured and specific checklist by HSCT teams, HSCT training for PICU personnel, and structured meetings between HSCT and PICU nurses.
    • Safety and activity of autologous T cells with enhanced NY-ESO-1-specific T-cell receptor (GSK3377794) in HLA-a*02(+) previously-treated and - untreated patients with advanced metastatic/unresectable synovial sarcoma: A master protocol study design (IGNYTE-ESO)

      D'Angelo, S. P.; Blay, J. Y.; Chow, W. A.; Demetri, G. D.; Thistlethwaite, Fiona C; Sen, S.; Razak, A. R. A.; Haanen, J.; Noujaim, J. C.; Johnson, M. L.; et al. (2020)
      Background: T cells modified to target NY-ESO-1 have shown encouraging activity in HLA-A*02+ patients with NY-ESO-1–positive synovial sarcoma. NY-ESO-1 is a cancer/testis antigen that is expressed across multiple tumor types and highly expressed in synovial sarcoma. NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR able to recognize NY-ESO-1 epitope in complex with HLA-A*02. Ongoing trials are evaluating GSK3377794 in multiple solid tumors and multiple myeloma. Methods: This study (NCT03967223) uses a Master Protocol design that allows investigation of GSK3377794 in multiple tumor types under the same protocol in separate substudies. The first two are single-arm substudies in patients with advanced metastatic or unresectable synovial sarcoma: treatment-naïve (1st line [1L], substudy 1; n = 10 planned) and progressing after anthracycline-based chemotherapy (2L+, substudy 2; n = 55 planned). Patients must be aged ≥10 years, have adequate organ function, ECOG performance status 0–1, measurable disease, and no central nervous system metastases. Excluded prior treatments include gene therapy with an integrating vector or NY-ESO-1–specific T cells, vaccine or targeting antibody, or allogeneic stem cell transplant. Patients will undergo leukapheresis and manufacture of GSK3377794; lymphodepletion then GSK3377794 infusion, followed by safety and disease assessments; and long-term follow-up for 15 years (under a separate protocol). The primary objective of substudy 2 is overall response rate per RECIST v1.1 by central independent review. Secondary objectives include time to response, duration of response, disease control rate, progression-free survival, overall survival, plus safety and tolerability. Exploratory objectives include assessment of the correlation of T-cell persistence with safety, clinical responses, and infused T-cell phenotype. Evaluation of quality of life and daily functioning of patients will also be assessed. Enrollment began in December 2019. These data are presented on behalf of the original authors with their permission. A similar presentation (P453) was presented at the SITC Annual Meeting, National Harbor, MD, USA, Nov 6–10, 2019. Funding: GlaxoSmithKline (208467) Clinical trial information: NCT03967223.
    • Safety and compliance of capecitabine and temozolomide in patients with advanced neuroendocrine tumours.

      Papaxoinis, Georgios; McCallum, Lynne; Nasralla, Magdy; Hubner, Richard A; McNamara, Mairéad G; Valle, Juan W; Mansoor, Was; Christie NHS Foundation, Manchester, UK (2016)
    • Safety and efficacy of bevacizumab plus standard-of-care treatment beyond disease progression in patients with advanced non-small cell lung cancer: the AvaALL randomized clinical trial.

      Gridelli, C; de Castro Carpeno, J; Dingemans, A; Griesinger, F; Grossi, F; Langer, C; Ohe, Y; Syrigos, K; Thatcher, Nick; Das-Gupta, A; et al. (2018-08-30)
      Bevacizumab treatment beyond progression has been investigated in breast and metastatic colorectal cancers. Avastin in All Lines Lung (AvaALL) is the first randomized phase 3 study of bevacizumab across multiple lines of treatment beyond progression in non-small cell lung cancer (NSCLC).
    • Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study.

      Crinò, Lucio; Dansin, Eric; Garrido, Pilar; Griesinger, Frank; Laskin, Janessa; Pavlakis, Nick; Stroiakovski, Daniel; Thatcher, Nick; Tsai, Chun-Ming; Wu, Yi-long; et al. (2010-08)
      BACKGROUND: Results of two phase 3 trials have shown first-line bevacizumab in combination with chemotherapy improves clinical outcomes in patients with advanced or recurrent non-squamous non-small-cell lung cancer (NSCLC). The SAiL (MO19390) study was undertaken to assess the safety and efficacy of first-line bevacizumab combined with standard chemotherapy regimens in clinical practice. METHODS: Between August, 2006, and June, 2008, patients with untreated locally advanced, metastatic, or recurrent non-squamous NSCLC were recruited to this open-label, single group, phase 4 study from centres in 40 countries. Eligible patients had histologically or cytologically documented inoperable, locally advanced, metastatic, or recurrent disease (stage IIIB-IV); an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, hepatic, and renal function. Patients received bevacizumab (7.5 or 15 mg/kg every 3 weeks) plus standard chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety; analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00451906. FINDINGS: At the final data cutoff (July 24, 2009), an ITT population of 2212 patients was assessed. The incidence of clinically significant (grade > or = 3) adverse events of special interest was generally low; thromboembolism occurred in 172 (8%) patients, hypertension in 125 (6%), bleeding in 80 (4%), proteinuria in 67 (3%), and pulmonary haemorrhage in 15 (1%). 57 (3%) patients died because of these adverse events, with thromboembolism (26 patients, 1%) and bleeding (17, 1%) as the most common causes. The most common grade 3 or higher serious adverse events deemed by investigators to be associated with bevacizumab were pulmonary embolism (28 patients; 1%) and epistaxis, neutropenia, febrile neutropenia, and deep vein thrombosis (all of which occurred in 13 patients [1%]). Bevacizumab was temporarily interrupted after 28 (2%) of 1347 bleeding events and 72 (7%) of 1025 hypertension events, and permanently discontinued after 110 (8%) bleeding events and 40 (4%) hypertension events. No new safety signals were reported. INTERPRETATION: Our results confirm the manageable safety profile of first-line bevacizumab in combination with various standard chemotherapy regimens for treatment of advanced non-squamous NSCLC. FUNDING: F Hoffmann-La Roche Ltd.
    • Safety and efficacy of nivolumab in challenging subgroups with advanced melanoma who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172)

      Schadendorf, D; Ascierto, PA; Haanen, J; Espinosa, E; Demidov, L; Garbe, C; Guida, M; Lorigan, Paul C; Chiarion-Sileni, V; Gogas, H; et al. (2019)
    • Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single arm, open-label, phase II study

      Nathan, P; Ascierto, PA; Haanen, J; Espinosa, E; Demidov, L; Garbe, C; Guida, M; Lorigan, Paul C; Chiarion-Sileni, V; Gogas, H; et al. (2019)
      BACKGROUND: Nivolumab has been widely studied in non-acral cutaneous melanoma; however, limited data are available in other melanoma subtypes. We report outcomes by melanoma subtype in patients who received nivolumab after progression on prior ipilimumab. PATIENTS AND METHODS: CheckMate 172 was a phase II, single-arm, open-label, multicentre study that evaluated nivolumab in patients with advanced melanoma who progressed on or after ipilimumab. Patients received 3 mg/kg of nivolumab, every 2 weeks for up to 2 years. The primary end-point was incidence of grade ³3, treatment-related select adverse events (AEs). RESULTS: Among 1008 treated patients, we report data on patients with non-acral cutaneous melanoma (n = 723 [71.7%]), ocular melanoma (n = 103 [10.2%]), mucosal melanoma (n = 63 [6.3%]), acral cutaneous melanoma (n = 55 [5.5%]) and other melanoma subtypes (n = 64 [6.3%]). There were no meaningful differences in the incidence of grade ³3, treatment-related select AEs among melanoma subtypes or compared with the total population. No new safety signals emerged. At a minimum follow-up of 18 months, median overall survival was 25.3 months for non-acral cutaneous melanoma and 25.8 months for acral cutaneous melanoma, with 18-month overall survival rates of 57.5% and 59.0%, respectively. Median overall survival was 12.6 months for ocular melanoma and 11.5 months for mucosal melanoma, with 18-month overall survival rates of 34.8% and 31.5%, respectively. CONCLUSIONS: The safety profile of nivolumab after ipilimumab is similar across melanoma subtypes. Compared with non-acral cutaneous melanoma, patients with acral cutaneous melanoma had similar survival outcomes, whereas those with ocular and mucosal melanoma had lower median overall survival. CLINICALTRIALS.
    • Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial.

      Melmed, S; Popovic, V; Bidlingmaier, M; Mercado, M; Van Der Lely, A; Biermasz, N; Bolanowski, M; Coculescu, M; Schopohl, J; Racz, K; et al. (2015-02-09)
      Background: A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study for acromegaly. Methods: We enrolled 155 complete or partially controlled patients (IGF-1 < 1.3 × upper limit of normal [ULN], and 2-h integrated GH < 2.5 ng/mL) receiving injectable somatostatin receptor ligand (SRL) for ≥ 3 months. Subjects were switched to 40 mg/d oral octreotide capsules (OOCs), and the dose escalated to 60 and then up to 80 mg/d to control IGF-1. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. Results: Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 < 1.3 × ULN and mean integrated GH < 2.5 ng/mL at the end of the core treatment period and 62% at the end of treatment (up to 13 mo). The effect was durable, and 85 % of subjects initially controlled on OOCs maintained this response up to 13 months. When controlled on OOCs, GH levels were reduced compared to baseline, and acromegaly-related symptoms improved. Of 102 subjects completing the core treatment, 86% elected to enroll in the 6-month extension. Twenty-six subjects who were considered treatment failures (IGF-1 ≥ 1.3 × ULN) terminated early, and 23 withdrew for adverse events, consistent with those known for octreotide or disease related. Conclusions: OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.
    • Safety and efficacy of the addition of lapatinib to perioperative chemotherapy for resectable HER2-positive gastroesophageal adenocarcinoma: a randomized phase 2 clinical trial

      Smyth, E; Rowley, S; Cafferty, F; Allum, W; Grabsch, H; Stenning, S; Wotherspoon, A; Alderson, D; Crosby, T; Mansoor, Was; et al. (2019)
      Importance: Perioperative chemotherapy and surgery are a standard of care for operable gastroesophageal adenocarcinoma. Anti-HER2 therapy improves survival in patients with advanced HER2-positive disease. The safety and feasibility of adding lapatinib to perioperative chemotherapy should be assessed. Objectives: To assess the safety of adding lapatinib to epirubicin, cisplatin, and capecitabine (ECX) chemotherapy and to establish a recommended dose regimen for a phase 3 trial. Design, Setting, and Participants: Phase 2 randomized, open-label trial comparing standard ECX (sECX: 3 preoperative and 3 postoperative cycles of ECX with modified ECX plus lapatinib (mECX+L). This multicenter national trial was conducted in 29 centers in the United Kingdom in patients with histologically proven, HER2-positive, operable gastroesophageal adenocarcinoma. Registration for ERBB/HER2 testing took place from February 25, 2013, to April 19, 2016, and randomization took place between May 24, 2013, and April 21, 2016. Data were analyzed May 10, 2017, to May 25, 2017. Interventions: Patients were randomized 1:1 open-label to sECX (3 preoperative and 3 postoperative cycles of 50 mg/m2 of intravenous epirubicin on day 1, 60 mg/m2 intravenous cisplatin on day 1, 1250 mg/m2 of oral capecitabine on days 1 through 21) or mECX+L (ECX plus lapatinib days 1 through 21 in each cycle and as 6 maintenance doses). The first 10 patients in the mECX+L arm were treated with 1000 mg/m2 of capecitabine and 1250 mg of lapatinib per day, after which preoperative toxic effects were reviewed according to predefined criteria to determine doses for subsequent patients. Main Outcomes and Measures: Proportion of patients experiencing grade 3 or 4 diarrhea with mECX+L. A rate of 20% or less was considered acceptable. No formal comparison between arms was planned. Results: Between February 2013, and April 2016, 441 patients underwent central HER2 testing and 63 (14%) were classified as HER2 positive. Forty-six patients were randomized; 44 (24 sECX, 20 mECX+L) are included in this analysis. Two of the first 10 patients in the mECX+L arm reported preoperative grade 3 diarrhea; thus, no dose increase was made. The primary endpoint of preoperative grade 3 or 4 diarrhea rates were 0 of 24 in the sECX arm (0%) and 4 of 20 in the mECX+L arm (21%). One of 24 in the sECX arm and 3 of 20 in the mECX+L arm stopped preoperative treatment early, and for 4 of 19 in the mECX+L arm, lapatinib dose was reduced. Postoperative complication rates were similar in each arm. Conclusions and Relevance: Administration of 1250 mg of lapatinib per day in combination with ECX chemotherapy was feasible with some increase in toxic effects, which did not compromise operative management.
    • Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial

      Moreno, V.; Barretina-Ginesta, M. P.; García-Donas, J.; Jayson, Gordon C; Roxburgh, P.; Vázquez, R. M.; Michael, A.; Antón-Torres, A.; Brown, R.; Krige, D.; et al. (2021)