Welcome to the August 2024 BTOG trainee newsletter, where we aim to provide you with updates relevant to trainees working in the thoracic oncology space. In terms of content, the trainee newsletter will seek to summarise the ‘hot-off-the-press’ landmark papers, list updates for trainee-led multicentre projects, and sign-post readers to useful educational/professional content.
We are proud to launch the BTOG One-Stop Resource Hub, a powerful new way to find resources from BTOG educational events and podcasts. Thank you to Adam Januszewski and Helen McDill who started this project when they were the BTOG Trainee Representatives.
Please do use the BTOG trainee group-chat on Slack to continue your thoracic cancer conversations in the meantime. Feel free to contact the BTOG trainee representatives, Anand and Gerard, at anand.sundaralingam@ndm.ox.ac.uk or g.walls@qub.ac.uk
The BTOG One-Stop Resource Hub is a brand new, comprehensive, searchable database of presentations and videos from BTOG education events (annual conferences, essential updates, study days, webinars, and podcasts), available exclusively to BTOG members.
Also included are Useful Core Resources: educational resources, guidelines, and other materials relevant to UK thoracic oncology professionals from organisations worldwide.
You can choose a speciality and then filter by tumour type, theme, and sub-category if you wish.
You can also search text in titles and descriptions of all our resources. You can search by keyword(s) e.g. ‘lung cancer screening’, or presenter surname, e.g. Popat.
Respiratory/Clinical Oncology
SEISMIC
Mediastinal lymph node (LN) staging is a crucial step in investigating patients with locally advanced non-small cell lung cancer (LA-NSCLC) who are eligible for curative therapies. This staging remains vital, even in the absence of avidity on PET-CT, as the sensitivity of PET-CT for mediastinal lymphadenopathy is <90%. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) differs from ‘blind-TBNA’ in that ultrasound-guidance is used to locate lymphadenopathy, which increases the probability of tumour tissue being acquired successfully. The value of systematic EBUS-TBNA combined with PET-CT for mediastinal staging compared with PET-CT alone has not yet been evaluated in locally advanced NSCLC. For patients receiving curative-intent radiotherapy, PET-negative lesions are typically omitted from the high-dose region of radiation and thus not treated. Identifying PET-occult mediastinal metastases with EBUS-TBNA could theoretically improve the efficacy of radiotherapy by ensuring the inclusion of all areas of disease during treatment planning.
In the Lancet Respiratory Medicine, Steinfort et al, present their findings from the SEISMIC study, an international multicentre single arm interventional study evaluating the impact of systematic mediastinal staging on target volumes in patients with NSCLC. Patients with locally advanced or unresectable NSCLC who were offered radical, or high-dose palliative radiotherapy were eligible. Following visual examination of LNs stations 2R, 2L, 4R, 4L and 7, any LN ≥6mm was sampled, starting with contralateral mediastinal nodes (i.e. N3). The primary outcome was the false-negative rate for detection of LN involvement by PET-CT, with secondary outcomes including the impact on dose received by PET-occult LNs, and the clinicoradiological factors associated with PET-occult LNs.
Of 191 consented patients, 155 underwent systematic EBUS staging. In 37% (n=57) of cases, EBUS and PET demonstrated discordant findings, with PET-occult LNs identified in 12% (n=18) of participants (i.e. false negatives). The only statistically significant risk factor for PET-occult disease was adenocarcinoma histology. PET-positive, EBUS-negative LNs were identified in 25% (n=39) participants (i.e. false positives), of whom 31 were down-staged and 20 underwent surgical resection. Pathological staging confirmed the EBUS-TBNA findings in all patients, verifying that the PET-CT findings were indeed false positives.
On average, only 10% of the volume of false-negative LN tissue received the therapeutic radiation dose of 60 Gy in retrospective re-plans. Additionally, in over 70% patients, these nodes would have received less than half of the therapeutic dose. For patients with false-positive LNs on PET-CT, statistically significant reductions were observed in doses to the oesophagus, heart, lungs and spine when retrospectively re-planned.
The authors conclude that systematic mediastinal staging has the potential to significantly impact the management of patients with locally advanced unresectable NSCLC. This approach enables the delivery of full dose radiation to false-negative lymph nodes or the reduction of dose to normal tissues in case of false-positive nodes. In addition, systematic EBUS staging may allow reconsideration of surgical options, for those initially deemed unresectable due to false-positive PET-CT findings. Overall, combining systematic EBUS staging with PET-CT may result in lower recurrence rates and lower radiotherapy toxicity rates compared to using PET-CT alone.
Diagram showing a bronchoscopy from Wikimedia
Expert Commentaries
The purpose of invasive nodal staging in lung cancer is three-fold:
1) Down-staging of any false positive lymph nodes on CT/PET
2) Confirmation of malignant lymph nodes positive on CT/PET
3) Identification of occult micro metastases in radiologically normal lymph nodes.
To achieve these goals with a staging EBUS requires a systematic examination of all thoracic lymph nodes starting with the contralateral hilum, followed by the contralateral mediastinum, central mediastinum, ipsilateral mediastinum and the ipsilateral hilum with sampling of both abnormal and normal-appearing lymph nodes. It is the sampling of normal lymph nodes where the greatest variation seems to exist in staging EBUS practice across the UK.
In patients with suspected lung cancer being worked up for curative-intent treatment with clearly malignant, unresectable thoracic lymph node disease (conglomerate, bulky, invasive lymphadenopathy) the prevalence of nodal metastases is considered to be 100% and therefore this cohort of patients have often been identified as requiring a diagnostic procedure only without the systematic nodal staging approach described above. The SEISMIC trial has now provided evidence that the systematic staging approach is also indicated in this cohort of patients as imaging alone will underestimate the volume & location of lymph lode metastases in just over one in ten patients, leading to significant impacts on the quality of radiotherapy planning.
In summary, the SEISMIC trial provides evidence that a systematic staging approach may be considered in this patient cohort, as imaging alone can underestimate the volume and location of lymph lode metastases in over 10% of cases. This discrepancy clearly has substantial implications for the quality of radiotherapy planning. Importantly however, SEISMIC did not report outcome data.
Prof Matthew Evison
Consultant Physician in Respiratory Medicine (Thoracic Oncology), Wythenshawe Hospital, Manchester University NHS Foundation Trust
Honorary Clinical Chair, Faculty of Biology, Medicine & Health, University of Manchester
This study expands further the indication for staging EBUS and also highlights the need for potential amendments to NICE guidance & the National Diagnostic Standards of Care published by the Lung Cancer Expert Group. NICE guidance recommends staging EBUS is systematic and that any lymph node that appears radiologically or sonographically abnormal should be sampled. This would support achieving goals 1 & 2 of a staging EBUS but perhaps less so the goal of detecting micrometastases in radiologically normal lymph nodes. To do this EBUS operators should also sample any lymph node measuring over 5mm in short axis, even if radiologically normal as was performed in the SEISMIC trial. The National Diagnostic Standards of Care states for patients with contiguous or conglomerate mediastinal lymphadenopathy (DSOC 3) ‘a staging EBUS may be required to define tumour extent’. With the results of the SEISMIC study, this may now need to become a clear recommendation.
A number of questions arise from the study:
- Do PET-occult LNs require full therapeutic doses?
- What is the impact on locoregional recurrence and survival when treating PET-occult LNs with full therapeutic doses?
- Could treating PET-occult LNs with full therapeutic doses adversely affect the immune system? This is particularly relevant for patients receiving consolidation immunotherapy after concurrent chemo-radiotherapy
- Will identifying false positive nodes lead to higher rates of resection? What are the implication in the era of neoadjuvant chemo-immunotherapy?
- What are the resource implications if systematic staging EBUS becomes standard of care?
Given these considerations, outcome data will be essential before altering national standards. Due to the challenges of running randomised trials to evaluate systematic EBUS staging, this data could be generated by including staging EBUS as a stratification factor in future trials for stage II–III NSCLC or through high-quality, prospective real-world studies.
Prof Corinne Faivre-Finn
Honorary Consultant Clinical Oncologist, The Christie NHS Foundation Trust
Professor of Thoracic Radiation Oncology, Division of Molecular and Cancer Sciences, University of Manchester
Medical Oncology
LAURA
This industry-sponsored, phase 3, randomised controlled trial in June’s edition of New England Journal of Medicine, evaluated the efficacy of indefinite adjuvant osimertinib compared with placebo among patients that completed definitive chemoradiation (concurrent or sequential) for NSCLC with a detected EGFR mutation. A total of 216 patients were recruited, predominantly at Asian centres (82%) between Aug 2018–July 2022) and the primary endpoint was progression-free survival (PFS), i.e. absence of disease progression and death.
The study met its primary endpoint in that the hazard ratio for PFS was 0.16 (p<0.001), which was comfortably under the pre-specified threshold of 0.53. In terms of preventing progression, this corresponded with an increase from 22% patients for the control arm to 75% for the experimental arm at 12 months. There were no differences in reported baseline characteristics between the groups to explain this finding. There was a higher rate of grade 3 toxicity in the experimental arm (35% vs 12%) which is expected, but no unexpected toxicities occurred.
Strengths of the study included independent central assessment of disease progression, which is a robust outcome measure for lung cancer trials, where discerning tumour growth from radiation-related pulmonary changes or infection is often challenging. Furthermore, the placebo control arm was appropriate, given that PACIFIC trial subgroup analyses revealed durvalumab immunotherapy did not benefit patients with EGFR mutations. Cross-over was permitted, with patients in the control arm given access to osimertinib on progression, in contrast with the ADAURA trial, a similar study in resectable disease, which will need to be taken into account in future overall survival analyses.
Several aspects of the study are controversial. Most importantly, PET-CT was not mandated for trial enrolment, which means some patients may have had occult (undetected) distant metastases, which would disproportionately impact the control arm in terms of progression outcomes, as these patients received no active treatment. Similarly, no method of minimal residual disease detection was incorporated in the trial (e.g. circulating tumour DNA) to enrich the trial cohort for patients at high risk of relapse. Combined with the fact that treatment is life-long, and a third of patients had a grade 3 toxicity at median follow-up of 2 years, gaining approvals for this treatment in unselected patients may be difficult in some countries. Akin to the PACIFIC study, there was a lack of radiotherapy data presented in the manuscript, but from the Supplemental Appendix it is apparent that almost a third of patients (31%) received out-dated radiotherapy techniques. Lastly, there is also the question of how applicable this largely Asian ethnicity data is to Black, Caucasian and other demographic groups.
The authors conclude that treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC.
The LAURA study is practice-changing and aligns to other studies utilising targeted therapies in the adjuvant setting (ADAURA, ALINA). The use of osimertinib life-long is akin to treating stage 3 disease as advanced disease. The financial, physical and psychological toxicities must be considered however and as a community we need to look at risk stratification or de-escalation strategies looking forward.
Dr Adam Januszewski
Consultant Medical Oncologist
St Bartholomew’s Hospital
Supportive Care
Image by Sabine van Erp from Pixabay
Pleural mesothelioma continues to comprise an incurable malignancy despite advances in surgical and non-surgical management. Among other factors, the guarded prognosis, challenging symptoms and occupation-linked aetiology mean mesothelioma is associated with a unique constellation of difficult psychological, mental health and quality of life problems. The recent study by Ejegi-Mehmeh et al sought to characterize the non-physical burden of this disease on patients and their carers using a semi-structured interview methodology. Ten patients with mesothelioma and eleven informal carers in the UK participated and the reflexive thematic analysis approach was used to evaluate the recorded dialogue.
Three broad categories of data arose from interviews: self-management strategies, professional input and social interactions. Participants reported that distractions, humour and family milestones were among the most useful self-management strategies. By contrast, distractions were less useful to carers and there was greater appetite for open discussion of the situation. Two thought-provoking specific items highlighted were exercise and religion. While great satisfaction was taken from exercise by some interviewees, reduced physical activity over time was an unwelcome and overt sign of deterioration. Similarly, while religious activities could bring spiritual comfort to those diagnosed with mesothelioma, it could also be a flashpoint between them and their carers, if only one was religious. Professionals such as oncology and palliative care nurses, doctors, mental health specialists, legal professionals and asbestos support groups are a source of psychological support. Participants expressed that their diagnosis led to them prioritising their relationships and time with friends/family, and that this could be a great counter against anger and frustration in relation to their asbestos exposure. Societal recognition of the injustice was identified by interviewees, and the risk of harmful preoccupation with this was also raised. Social media was reported to be of value in receiving encouragement.
The authors noted that overall, there was evidence of differing needs between those with the disease and those informally caring for them, and that future interventions should cater to both groups. They also emphasise that many patients may also have had caring responsibilities, which can bring addition complexity to the psychological burden of a mesothelioma diagnosis.
In summary, this rich dataset showcases the utility of both qualitative research and studies of patient perception, opinion or experience. A linked quantitative survey conducted by the same investigators is recommended reading, and together with this qualitative research, exemplify how ‘mixed methods’ approaches may be able to advance thoracic oncology. Clinically, the accounts of the people diagnosed with mesothelioma and their carers in this study provide a wealth of insights into the psychological aspects of lived experience, from both perspectives, and academically, will inform the design of future patient-centered interventions in mesothelioma.
A useful insight into this understudied patient and carer population, revealing differences between patients and carers yet similar concerns and coping mechanisms to lung cancer patients in this small study. Interesting findings were gender differences in participation, compensation levels and involvement with/usefulness of social media/online groups. Simple activities e.g. walking, being outdoors, social contact with family and friends improved physical and mental wellbeing. Support recognised and valued from CNS, other healthcare professionals and unusually compared with other cancer types, asbestos support groups/lawyers. Important for all HCPs, not just CNSs, to support and signpost and this is highly valued by patients and carers. Help with form completion/submission and receiving compensation helped ease anxiety and burden for those able to benefit. Interested to see further work in this area including coping methods for those without support from partners, carers or family members.
Sally Hall
BTOG Steering Committee members (Patient Advocate)
Janette Rawlinson
BTOG Steering Committee members (Patient Advocate)
Dates for your diary
- Conference of American Association for Bronchology and Interventional Pulmonology (AABIP 2024) – 22nd – 24th August, Charlotte, NC., USA
- WCLC 2024 – 7th – 10th September, San Diego, CA, USA
- ESMO Congress 2024 – 13th – 17th September, Barcelona, Spain
- BTOG Webinar: ECLC/ESMO 2024 Update – TBC September, Online
- International Thymic Malignancy Interest Group 2024 – 30th – 31st October, Yokohama, Japan
- ETOP Residential Workshop – 30th October – 1st November, Barcelona, Spain (deadline 31st July)
- ETOP Annual Meeting – 1st – 2nd November, Barcelona, Spain (deadline 30th August)
- 6th International Joint Meeting on Thoracic Surgery – 20th – 22nd November, Barcelona, Spain
- BTS Winter Meeting – 27th – 29th November, London
- Mesothelioma Essential Update (BTOG & Mesothelioma UK) – 9th December, London