Welcome to the November 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.
#BTOG25 Scholarship applications are now open
You can now submit your applications for a scholarship to attend the BTOG annual conference, applications must be received by 31st December 2024.
Applicants must:
- Be a healthcare professional involved in care or treatment of patients with thoracic malignancies or involved in research in the UK and
- Be an allied health professional, nurse specialist, radiographer or trainee doctor up to and including specialist registrar grade or consultant and
- Submit an abstract to the annual conference and will attend annual conference.
Mark your calendar: At BTOG 2025 on Monday 3 March 2025 from 10:00 – 11:00 we will host a BTOG Trainees Networking/Introduction.
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
Respiratory
Accuracy of Clinical Staging for Stage III-Single-station N2 NSCLC
Image from Wikimedia Commons used under a CC BY-SA 3.0 License.
Management of Stage III N2 NSCLC is complex, this is in part driven by the definition of ‘surgically resectable.’ At present there is no standardised definition for this term, and it remains the subject of much interest and debate at thoracic oncology conferences. Within UK practice, determination of single station (ssN2) vs multi station (msN2) has been used as a criteria for determining surgical resectability. This is partly due to the reported post-operative outcomes for patients with ssN2 vs msN2 in the international thoracic surgical database, though it should be stressed that there was no comparator group of non-surgical treatments in the IASLC database, so it is difficult to draw conclusions on the optimal management for ssN2 or msN2 disease. That being said accurate determination of ssN2 vs msN2 is prognostically important, but a further complicating element in the debate is the apparent discordance between clinical staging and final pathological staging in NSCLC.
In the Journal of Thoracic Oncology Craig and colleagues describe the findings from their multicentre retrospective cohort study comparing clinical staging of stage III ssN2 NSCLC to pathological staging. The study was conducted in two cohorts: cohort A comprised of consecutive patients presenting to the Greater Manchester Cancer Alliance from 2015-2018 and cohort B comprised of multiple UK centres outside of Greater Manchester from 2016-2020, to serve as a validation cohort. All patients required CT, PET and a staging EBUS pre-operatively for inclusion in the study. Their primary outcome measure of interest was the accuracy of clinical staging for ssN2 disease compared to the gold standard of pathological staging.
56 patients were included in cohort A and 59 patients in cohort B, both populations were broadly similar. Across the combined study population, 38/115 (33%, 19 in each cohort) were upstaged on pathological staging, giving an overall diagnostic accuracy for clinically staging ssN2 of 67%. Most patients had only a single radiologically abnormal lymph node (LN) on CT or PET (101/115, 88%) indicating almost all the missed msN2 cases had radiologically occult LN metastases (37/38, 97%). The main reasons for misdiagnosing cases as ssN2 was due to: accessible LN but not sampled due to normal appearance (15/38, 40%, of which 4 occurred in Cohort A and 11 in Cohort B), inaccessible LN group (13/38, 34%) and false-negative EBUS sampling (10/38, 26%). The only variable thought to be associated with a greater risk of pathological upstaging to msN2 was squamous cell cancer subtype, which bordered on statistical significance (p = 0.052).
The authors conclude that clinical staging of ssN2 is often inaccurate, and this is a recognised limitation of radiology and minimally invasive staging techniques. Therefore, determining surgical resectability should not be contingent upon demonstrating ssN2 vs msN2 and a standardised definition for resectable stage III NSCLC is much needed.
Establishing the pathological nodal status before treatment in non-metastatic disease enables a tailored approach, typically involving (a) surgical resection (N0), (b) surgical resection with neoadjuvant chemo-immunotherapy and/or adjuvant therapy (N1/N2), or (c) combination chemoradiotherapy (N2 ± N3).
The proposed 9th edition TNM classification is set for adoption in the UK in January 2025, with an updated framework emphasising a refined approach to nodal staging recognising prognostic differences between single- and multi-station N2 disease. This timely study by Evison and colleagues offers important insights and critical nuances in how these patients are managed.
First, the study underscores the ongoing need for high-quality, systematic intra-operative mediastinal lymph node dissection in all surgical cases. In 60% of missed msN2 cases, either lymph nodes were inaccessible, or EBUS sampling produced false negatives. While FN’s may stem from insufficient tissue, it’s important to recognise the lower sensitivity of EBUS—estimated around 50%—in a radiologically negative mediastinum. Occult metastases often involve microscopic disease that can be unevenly distributed within the lymph node, complicating detection.
Second, comprehensive systematic nodal staging during EBUS is crucial. In 40% of missed msN2 cases, accessible lymph nodes were not sampled. Sampling decisions were based on Fujiwara’s 2010 study in Chest, under the assumption that normal-appearing nodes were unlikely to harbour metastases. Certain EBUS features—such as size <10mm, shape, indistinct margins, homogeneity, and central hilar structure—can indicate benign nodes. The ESTS guidelines recommend a structured approach, sampling any accessible lymph node >5mm in short axis. This strategy, reinforced by recent SEISMIC trial findings, indicate that systematic LN sampling provides more granular nodal staging than targeted sampling. Of course, additional complexity may arise with TNM 9, including questions on which N2 station to sample first and whether the TBNA needle should be changed when moving from one N2 station to another.
Finally, the role of surgery for msN2 NSCLC remains debated. Patients with ssN2 are typically better surgical candidates due to the localised extent of their disease, especially when neoadjuvant therapy is included in the treatment plan. However, in this study, 97% of patients with missed msN2 disease had radiologically negative lymph nodes. Combined with the lower accuracy of EBUS in this population, this raises the question of whether the distinction between ssN2 and msN2 should be an absolute criterion for surgery or no-surgery. While msN2 patients are often directed toward combined chemoradiotherapy, a multidisciplinary team should carefully consider surgery for those with small, well-defined, and technically resectable lymph nodes.
Dr Ricky Thakrar
Consultant Chest Physician, University College London Hospitals NHS Foundation Trust
Honorary Associate Professor, Division of Medicine, University College London
Surgery
MARS 2
Image from Wikimedia Commons used under a CC BY-SA 3.0 License.
Malignant pleural mesothelioma (MPM) represents one of the most aggressive cancers, with an average lifespan from diagnosis of just 9-12 months. There has been modest impact on survival from systemic anticancer therapies (SACTs) in MPM. Therefore, surgery to remove all visible disease is recommended in a number of guidelines. There are two main surgical techniques to achieve macroscopic resection. The first is an extra-pleural pneumonectomy (EPP), an extensive operation that resulted in poorer outcomes for patients when assessed in the original MARS study. The second is a less invasive operation which involves a pleurectomy decortication (parietal and visceral pleurectomy to remove gross tumour extended to include resection of diaphragm or pericardium where required, EPD). This has replaced EPP as the principle surgical intervention of choice in MPM, despite absence of randomised evidence to support its use.
In Lancet Respiratory Medicine Lim and colleagues describe findings from the MARS 2 study, a multicentre randomised controlled trial of EPD and chemotherapy compared to chemotherapy alone in patients with resectable MPM. The primary outcome was overall survival and secondary outcomes included progression free survival (PFD), serious adverse events (SAEs) and health related quality of life (HRQoL).
335 patients underwent randomisation (surgery + chemotherapy = 169, chemotherapy alone = 166). 288 (86%) of the trial participants were diagnosed with epithelioid mesothelioma whilst 29 (9%) were biphasic and 11 (3%) were sarcomatoid. All operations were undertaken in 5 surgical centres (4 deemed centres of excellence and 1 a non-expert centre, by design). The majority of operations (89%) in the surgical arm included resection of diaphragm and/or pericardium (ie. EPD).
Both the in-hospital mortality and 30-day mortality for those in the surgical arm were 4% (n = 6), whilst the 90-day mortality was 9% (n= 14). The median survival in the surgery with chemotherapy arm was 19.3 months, compared to 24.8 months in the chemotherapy alone arm. Survival appeared to be poorer in the surgical arm across all MPM histological subtypes. No differences were observed in PFS between surgery or chemotherapy groups (median 10.6 months vs 11 months, respectively). A greater number of SAEs were observed in the surgical group (318 vs 169) with a significant number of more cardiac and respiratory disorders in the surgical arm. Patients in the surgical arm had poorer HRQoL scores compared to the chemotherapy group (mean difference -0.14 median EQ-5D score, p<0.0001).
The authors conclude that EPD was associated with worse survival, more SAEs and poorer HRQoL compared to chemotherapy alone in patients with resectable MPM.
Surgical trials are incredibly difficult to undertake, and even more so when a highly morbid operation is in one treatment arm and not the other. The authors and triallists of MARS 2 must be congratulated for their perseverance in completing this important study which took almost six years to recruit. The trial design was driven by a need for high-quality evidence concerning the effectiveness of lung-sparing surgery in mesothelioma following results of the MARS trial published in 2011 showing no benefit of extra-pleural pneumonectomy (EPP) with chemotherapy and radiotherapy over chemotherapy. Reports from case series of patients undergoing EPD had also suggested prolonged survival in highly selected patients but until the publication of MARS 2, EPD had never been studied as part of a randomised trial.
Along with the MARS trial, MARS 2 also shows no benefit of cytoreductive lung-sparing surgery. In spite of some of the criticisms of the study (e.g. pertaining to inclusion criteria, trial design and extent of surgery performed), it would be difficult to ignore the results of both studies and justify offering cytoreductive surgery to patients with mesothelioma. However, with the recent advances made in systemic treatments and better understanding of the disease, it is possible that there may be a future surgical trial within the context of novel systemic treatment as the search for a cure for mesothelioma continues.
Miss Carol Tan
Consultant Thoracic Surgeon
Guy’s Hospital, London
MARS Trial Surgical Coordinator
MARS 2 Trial Steering Committee
Survivorship
ESPATUE
A survivorship study was recently published by the ESPATUE investigators, who sought to compare trimodality and bimodality definitive treatment of stage III NSCLC. ESPATUE was a German multicentre RCT comparing chemoradiotherapy (45Gy BD) plus surgery (CH+RT+surg) with chemoradiotherapy (45 Gy BID + ~22Gy OD) alone (CH+RT) in resectable stage III NSCLC cases following 3 cycles of induction chemotherapy. Randomisation (1:1) occurred during week 3 following re-evaluation of operability, based on MDT recommendations. The trial primary endpoint was overall survival but the results were not powered for this since the trial was closed early regarding slow recruitment. The main results for the 161 randomised ECOG 0-1 patients were published in 2015, revealing that there was no difference in progression-free or overall survival.
In this late outcomes publication, patients with >10 years of follow-up were invited to participate in a survivorship sub-study including imaging, bloods, cardiac and respiratory investigations, late toxicity clinical assessments and quality of life questionnaires. Of 37 surviving pts, 31 agreed to participate – n=13 CH+RT; n=12 in CH+RT+surg; n=6 not randomised. The authors found that significant (G3-4) long-term toxicities were rarely observed and were balanced between the two main study arms. Similarly, global QOL score analysis did not show a signal favouring either definitive locoregional approach, and a late-onset decline (compared to baseline and 1 year) was not observed. Specific EORTC tool responses for fatigue, pain, dyspnoea and financial toxicity, and physical, emotional, cognitive and social function were not different between the two arms.
Focussing on COPD and heart failure severity within the cohort specifically, while there was no major difference for the former between the arms, it could be viewed that cardiac disease was more prevalent during the follow-up of patients who had received radiotherapy (including those not randomised). The rates of heart failure for CH+RT were 4/13 (31%), compared with 1/14 (7%) for CH+RT+surg. Although the severity was only grade 1-2 this may be perceived to be significant for patients given the chronicity, additional tablets & outpatient appointments and investigations, plus heart failure has the capacity to compound other acute medical illnesses.
However, without any details on the baseline cardiac risk factors or diseases and heart/substructure radiation doses, and given the small numbers of patients included, it is important not to over-interpret these heart failure data. The included population also incurred the greatest follow-up time in which new cardiac events could occur. In relation to radiotherapy, planning was 3D-conformal, which generally restricts applicability in the current era of intensity-modulated radiotherapy. It is also perhaps worth highlighting that these patients had good fitness (PS 0-1 and medical operable), and therefore if indeed accurate, the prevalence of post-RT heart failure in this study may be an underestimate the risk in the real-world RT population.
Overall, this study provides important evidence regarding the late effects of surgery and radiotherapy. This is the first comprehensive survivorship study of stage III NSCLC treated within a randomized multimodality trial.
DOI: 10.1002/ijc.35131
This is a small but important study as it provides the thoracic oncology community with evidence regarding the long term effects of our two main radical treatments. For those scenarios where choice of definitive treatment is difficult, these results can be used to reassure the patient that survivorship in the long-term is approximately equal. This effort by the ESPATUE team sets a new benchmark for non-metastatic NSCLC clinical trials by generating a template for future studies of long term effects. There are ongoing questions about the cardiotoxicity of high-dose radiotherapy, but there are insufficient data to take any firm conclusions from this very modest sample size. Lastly, it will be important to see the same long-term outcome reports in the era of combined immunotherapy – both for surgery and radiotherapy.
Mr Rory Beattie
Consultant Thoracic Surgeon
Royal Victoria Hospital Belfast
and
Dr Jonathan McAleese
Consultant Clinical Oncologist
Northern Ireland Cancer Centre
Medical Oncology
ADRIATIC
Image from Wikimedia Commons used under a CC BY-SA 3.0 License.
The combination of immune checkpoint inhibition with chemoradiation in limited stage small cell lung cancer (SCLC) was evaluated recently, following positive results in non-metastatic NSCLC (PACIFIC trial) and in extensive stage SCLC concurrently with chemotherapy (CASPIAN and Impower133 trials).
ADRIATIC is an ongoing industry-sponsored, multicentre, phase 3, double-blind, placebo-controlled trial. Patients were randomised (1:1) to receive two years of 4-weekly durvalumab (anti-PD-L1) following completion of chemoradiation, provided disease was at least stable, there was no grade ≥2 toxicities from chemoradiation and they remained ECOG PS 0-1. The dual primary endpoints were overall survival and progression-free survival (RECIST 1.1).
Among 530 patients randomised, durvalumab led to improved overall survival compared with placebo (56 months vs 33 months, hazard ratio 0.73, p=0.01). It should be noted that fewer patients in the experimental arm received next-line chemo- (31% vs 43%) or immunotherapy (6% vs 12%). Progression-free survival (17 months vs 9 months, hazard ratio 0.76, p=0.02) was also increased. The experimental arm outperformed the control arm in terms of the rate of complete/partial response or stable disease (56% vs 49%). As both primary endpoints were met, the trial was therefore deemed to be a positive trial.
In terms of toxicity, the incidence of grade 3–4 adverse events was 24% in both study arms, although there were slightly more treatment-related discontinuations (16% vs 11%) in the experimental arm. The rate of any-grade, all-cause pneumonitis was higher with durvalumab than placebo (38% vs 30%) but grade 3–4 pneumonitis occurred in 3% of both study groups. There was one death due to pneumonitis (experimental arm). That both the median number of cycles and dose intensity were similar between the arms (9 and 100% respectively) reflects that overall the encouraging safety profile data of adjuvant durvalumab.
Although not specifically powered in the study design, subgroup analysis for overall survival revealed particular benefit for adjuvant durvalumab when the concurrent platinum backbone was carboplatin (as opposed to cisplatin), and when treatment was initiated <14days after chemoradiation completed (as opposed to 15–42 days). Subgroup analyses also indicated a benefit for durvalumab regardless of chemoradiation schedule (twice-daily or once-daily) and whether prophylactic cranial irradiation was administered or not, both of which are ongoing areas of debate.
As well as the common trial population differences with the real-world of greater ECOG 0–1 and younger patients, ADRIATIC was conducted in White/Asian patients almost exclusively, there was a predominance of once-daily radiotherapy and patients mostly had stage III disease. These aspects of the trial cohort may restrict the application of the results outside these settings. Two years of adjuvant treatment is longer than most adjuvant treatments in Oncology, and the investigators have justified this as this is the period when most relapses occur. Whether this period could be altered for the four emerging SCLC molecular subtypes remains to be evaluated.
Other strengths of the study include how radiological disease control status was adjudicated by blinded independent central review, and quality of life assessments were collected (not reported). There was also an additional arm for combination of durvalumab with tremelimumab (anti-CTLA-4) arm but that was not reported.
Despite high rates of relapse in limited stage SCLC, currently there are no approved adjuvant therapies – hence ADRIATIC is considered a landmark study that is likely to be a practice-changing study, pending national approvals.
ADRIATIC is an exciting step forward in the field of limited-stage small cell lung cancer, where there have been no practice-changing trials for 20 years. Adjuvant durvalumab has a clear survival benefit, and hopefully future quality of life and translational analyses will help us better understand how immunotherapy can be combined with chemoradiation in this setting. Reassuringly, akin to PACIFIC, radiation pneumonitis was not significantly increased with the combination. Unlike PACIFIC however, the role of PD-L1 expression is less clear, so alternate biomarkers to help us know which patients this treatment will be effective (and not effective) for.
Professor Fiona Blackhall
Consultant Medical Oncologist
The Christie NHS Foundation Trust
BTOG Events
Noticeboard
Interested in being a lung and melanoma medical oncologist with time for research and development of immunotherapy lead role?
Fancy relocating to beautiful Cheltenham and joining a fun/friendly team?
Check out this job advert and apply/get in touch if you’re interested:
Apply here before 1 December 2024.
(Disclaimer: BTOG has not validated the fun/friendliness of the team).
Other event dates for your diary
- 6th International Joint Meeting on Thoracic Surgery – 20th – 22nd November, Barcelona, Spain
- BTS Winter Meeting – 27th – 29th November, London
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.