CompARE: study protocol for a phase III randomised controlled platform trial comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer.

BACKGROUND: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival. METHODS: CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention. Eligible OPC patients include those with human papillomavirus (HPV) negative, T1-T4, N1-N3 or T3-4, N0, or HPV positive N3, T4, or current smokers (or ≥ 10 pack years previous smoking history) with T1-T4, N2b-N3. CompARE was originally designed with four arms (one control [arm 1] and three experimental: arm 2-induction chemotherapy followed by arm 1; arm 3-dose-escalated radiotherapy plus concomitant cisplatin; and arm 4-resection of primary followed by arm 1). The three original experimental arms have been closed to recruitment and a further experimental arm opened (arm 5-induction durvalumab followed by arm 1 and then adjuvant durvalumab). Currently recruiting are arm 1 (control): standard treatment of 3-weekly cisplatin 100 mg/m2 or weekly 40 mg/m2 with intensity-modulated radiotherapy using 70 Gy in 35 fractions ± neck dissection determined by clinical and radiological assessment 3 months post-treatment, and arm 5 (intervention): one cycle of induction durvalumab 1500 mg followed by standard treatment then durvalumab 1500 mg every 4 weeks for a total of 6 months. The definitive and interim primary outcome measures are overall survival time and event-free survival (EFS) time, respectively. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complication rates, and cost-effectiveness. The design anticipates that after approximately 7 years, 84 required events will have occurred to enable analysis of the definitive primary outcome measure for this comparison. Planned interim futility analyses using EFS will also be performed. DISCUSSION: CompARE is designed to be efficient and cost-effective in response to new data, emerging new treatments or difficulties, with the aim of bringing new treatment options for these patients. TRIAL REGISTRATION: ISRCTN ISRCTN41478539 . Registered on 29 April 2015.

Electrochemotherapy vs radiotherapy in the treatment of primary cutaneous malignancies or cutaneous metastases from primary solid organ malignancies: A systematic review and narrative synthesis.

BACKGROUND: Electrochemotherapy has gained international traction and commendation in national guidelines as an effective tool in the management of cutaneous malignancies not amenable to surgical resection. Despite this, no level 5 evidence exists comparing it to radiotherapy in the treatment of cutaneous malignancies. This systematic review aimed to examine the literature directly and indirectly comparing electrochemotherapy and radiotherapy in the treatment of primary cutaneous malignancies or cutaneous metastases from primary solid organ malignancies. MATERIALS & METHODS: The protocol for this review was registered on the PROSPERO International Prospective Register of Systematic Reviews with the protocol ID CRD42021285415. Searches of MEDLINE, Embase, CINAHL, CENTRAL and ClinicalTrials.gov databases were undertaken from database inception to 28 December 2021. Studies in humans comparing treatment with electrochemotherapy to radiotherapy and reporting tumour response with a minimum four week follow-up were eligible. Risk of bias was assessed using the ROBINS-I tool. Results are provided as a narrative synthesis. RESULTS: Two case series with a total of 92 patients were identified as relevant to this study. Both case series examined patients with cutaneous squamous cell carcinoma. One case series examined elderly patients with predominantly head/neck lesions. The other examined younger patients with predominantly limb lesions who had cutaneous squamous cell carcinoma directly attributable to a rare skin condition. CONCLUSION: There is little literature presenting comparative data for electrochemotherapy and radiotherapy in the treatment of primary cutaneous malignancies or cutaneous metastases. Included studies were marred by serious risk of bias particularly due to confounding. The inherent bias and heterogeneity of the included studies precluded synthesis of a consolidated comparison of clinical outcomes between the two therapies. Further research is required in this domain in the form of clinical trials and observational studies to inform guidelines for electrochemotherapy treatment.

Optimal tool design in micro-milling of difficult-to-machine materials.

The limitations of significant tool wear and tool breakage of commercially available fluted micro-end mill tools often lead to ineffective and inefficient manufacturing, while surface quality and geometric dimensions remain unacceptably poor. This is especially true for machining of difficult-to-machine (DTM) materials, such as super alloys and ceramics. Such conventional fluted micro-tool designs are generally down scaled from the macro-milling tool designs. However, simply scaling such designs from the macro to micro domain leads to inherent design flaws, such as poor tool rigidity, poor tool strength and weak cutting edges, ultimately ending in tool failure. Therefore, in this article a design process is first established to determine optimal micro-end mill tool designs for machining some typical DTM materials commonly used in manufacturing orthopaedic implants and micro-feature moulds. The design process focuses on achieving robust stiffness and mechanical strength to reduce tool wear, avoid tool chipping and tool breakage in order to efficiently machine very hard materials. Then, static stress and deflection finite element analysis (FEA) is carried out to identify stiffness and rigidity of the tool design in relation to the maximum deformations, as well as the Von Mises stress distribution at the cutting edge of the designed tools. Following analysis and further optimisation of the FEA results, a verified optimum tool design is established for micro-milling DTM materials. An experimental study is then carried out to compare the optimum tool design to commercial tools, in regards to cutting forces, tool wear and surface quality.

Manufacturing of Soft Contact Lenses Using Reusable and Reliable Cyclic Olefin Copolymer Moulds.

We present experimental evidence of reusable, reliable cyclic olefin copolymer (COC) moulds in soft contact lens manufacturing. The moulds showed high performance surface roughness characteristics despite >20 kW exposure to 365 nm ultraviolet (UV) light from repeated use. Ultra-precision manufacturing techniques were used to fabricate transparent COC mould inserts and to produce soft contact lenses from liquid monomer compositions. Both polymer and silicone hydrogels were fabricated with more than 60 individual uses of the moulds. White light interferometry measured the surface roughness (Sa) of the COC moulds to be almost unchanged before and after repeated use (Sa 16.3 nm before vs. 16.6 nm after). The surface roughness of the prototyped lenses and that of commercially available soft contact lenses were then compared by white light interferometry. The surface roughness of the lenses was also nearly unchanged, despite undergoing more than 60 uses of the COC moulds (lens Sa 24.4 nm before vs. after Sa 26.5 nm). By comparison the roughness of the commercial lenses ranged from 9.3−28.5 nm, including conventional and silicone lenses, indicating that the reusable COC moulds produced competitive surface properties. In summary, COC moulds have potential as reusable and reliable mould inserts in the manufacturing of soft contact lenses, yet maintain high quality optical surfaces even after sustained exposure to UV light.

Precision micro-milling process: state of the art.

Micro-milling is a precision manufacturing process with broad applications across the biomedical, electronics, aerospace, and aeronautical industries owing to its versatility, capability, economy, and efficiency in a wide range of materials. In particular, the micro-milling process is highly suitable for very precise and accurate machining of mold prototypes with high aspect ratios in the microdomain, as well as for rapid micro-texturing and micro-patterning, which will have great importance in the near future in bio-implant manufacturing. This is particularly true for machining of typical difficult-to-machine materials commonly found in both the mold and orthopedic implant industries. However, inherent physical process constraints of machining arise as macro-milling is scaled down to the microdomain. This leads to some physical phenomena during micro-milling such as chip formation, size effect, and process instabilities. These dynamic physical process phenomena are introduced and discussed in detail. It is important to remember that these phenomena have multifactor effects during micro-milling, which must be taken into consideration to maximize the performance of the process. The most recent research on the micro-milling process inputs is discussed in detail from a process output perspective to determine how the process as a whole can be improved. Additionally, newly developed processes that combine conventional micro-milling with other technologies, which have great prospects in reducing the issues related to the physical process phenomena, are also introduced. Finally, the major applications of this versatile precision machining process are discussed with important insights into how the application range may be further broadened.

A multi-centre survey reveals variations in the standard treatments and treatment modifications for head and neck cancer patients during Covid-19 pandemic.

BACKGROUND: The onset of the COVID-19 pandemic necessitated rapid changes to the practice of head and neck oncology in UK. There was a delay between the onset of the pandemic and the release of guidelines from cancer societies and networks, leading to a variable response of individual centres. This survey was conducted to assess the pre-Covid-19 pandemic standard of practice for head and neck oncology patients and the treatment modifications introduced during the first wave of the pandemic in UK. METHODOLOGY: The UK National Cancer Research Institute (NCRI) Head and Neck Clinical Studies Group initiated a multi-centre survey using questionnaire to investigate the effect on feeding tube practice, radiotherapy (RT) fractionation and volumes, use of chemotherapy in the neo-adjuvant, concurrent and palliative setting, the use of immunotherapy in the palliative setting, access to radiology and histopathology services, and availability of surgical procedures. RESULTS: 30 centres were approached across UK; 23 (76.7%) centres responded and were included in the survey. There were differences in the standard practices in feeding tube policy, RT dose and fractionation as well as concurrent chemotherapy use. 21 (91%) participating centres had at least one treatment modification. 15 (65%) centres initiated a change in radical RT; changing to either a hypofractionation or acceleration schedule. For post-operative RT 10 centres (43.5%) changed to a hypofractionation schedule. 12 (52.2%) centres stopped neo-adjuvant chemotherapy for all patients; 13 (56.5%) centres followed selective omission of chemotherapy in concurrent chemo-radiotherapy patients, 17 (73.9%) centres changed first-line chemotherapy treatment to pembrolizumab (following NHS England's interim guidance) and 8 (34.8%) centres stopped the treatment early or offered delays for patients that have been already on systemic treatment. The majority of centres did not have significant changes associated with surgery, radiology, histopathology and dental screening. CONCLUSION: There are variations in the standard of practice and treatment modifications for head and neck cancer patients during Covid-19 pandemic. A timely initiative is required to form a consensus on head and neck cancer management in the UK and other countries.

Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.

BACKGROUND: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy. METHODS: We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080. FINDINGS: Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007). INTERPRETATION: Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. FUNDING: Cancer Research UK.

Developing a complex intervention for the outpatient management of incidentally diagnosed pulmonary embolism in cancer patients.

BACKGROUND: Most patients with pulmonary embolism (PE) spend 5-7 days in hospital even though only 4.5% will develop serious complications during this time. In particular, the group of patients with incidentally diagnosed PE (i-PE) includes many patients with low risk features potentially ideal for outpatient management; however the evidence for their optimal management is lacking hence relative practices may vary considerably. We describe the development process, components, links and function of a nurse-led service for the management of patients with i-PE, developed in accordance to the UK Medical Research Council complex intervention guidance. METHODS: Phase 0 (Theoretical underpinning): The Pulmonary Embolism Severity Index (PESI) was selected for patient risk assessment and the American Society of Clinical Oncology (ASCO) guideline for the management of PE in cancer patients (2007) was selected as quality measure. Historical registry and audit data from our centre regarding i-PE incidence and management for the period between 2006 and 2009 illustrating the then current practices were reviewed. Phase 1 (Modelling): Modelling of the pathway included the following: a) Identification of training needs, planning and implementation of training schemes and development of transferable competencies and training materials. b) Mapping patient pathways and flow and c) Production of key documentation and Standard Operating Procedures for the delivery of the service. RESULTS: Phase 2 (Implementation and testing of the intervention): During the initial 12 months of implementation, remedial action was taken to address identified deficiencies regarding patient referral to the pathway, compliance with treatment protocol, patient follow up, selection challenges from the use of PESI in cancer patients and challenges regarding the "first-pass" identification of i-PE. CONCLUSION: We have developed and piloted a complex intervention to manage cancer patients with incidental PE in an outpatient setting. Adherence to evidence- based care, improvement of communication between professionals and patients, and improved quality of data is demonstrated.