Trainee Enews April 2024

Welcome to the April 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.

The dedicated networking and introduction session for trainees at the BTOG Annual Conference is on Wednesday 17 April between 10am and 11am in Meeting Room 1 on Level 3, we look forward to seeing you all there!

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

OPTIMUM

Case courtesy of Frank Gaillard, Radiopaedia.org. From the case rID: 21736

Malignant pleural effusions (MPE) are a frequent and often debilitating consequence of thoracic cancers. Patients with MPEs have a number of options for achieving definitive symptom control. These include the insertion of an indwelling pleural catheter (IPC) and subsequent domiciliary drainage with optional outpatient talc slurry, or a chest drain followed by talc pleurodesis, which necessitates a hospital admission. Each has its own advantages and disadvantages. To date, the impact of either approach on health-related quality of life (HRQoL), as a primary outcome has not been studied.

In the European Respiratory Journal Sivakumar et al present their findings from the OPTIMUM study, a multicentre RCT of chest drain + talc slurry vs IPC +talc slurry. To be eligible patients required an ECOG PS of at least 3, with an expected survival >3 months and those with chemotherapy naïve small cell lung cancer or lymphoma were excluded. Patients in the IPC arm would be offered talc pleurodesis if drain output had diminished with no evidence of trapped lung and the IPC was removed 14 days after initial insertion, if pleurodesis was deemed successful. Those in the chest drain arm received usual standard of care.

Out of 548 screened patients, 142 were randomised to IPC (n=70) or chest drain (n=72). The majority were PS 1-2 with lung cancer the most common malignancy subtype, followed by breast and mesothelioma. Primary outcome data was available in 58/70 IPC and 56/72 chest drain participants. Global health status on EORTC QLQ-C30 improved in both groups at day 30 compared to baseline in IPC and chest drain groups (mean difference 13.11, p = 0.001 and 10.11, p = 0.001, respectively). There was no significant between group differences in HRQoL, dyspnoea or chest pain.

 

The authors conclude that both interventions, IPC +/- talc slurry and chest drain +/- talc slurry result in an improvement in HRQoL, with little difference between either approach. They recommend adopting a patient-centred approach that considers their unique health, psychological and social circumstances.

 

DOI: 10.1183/13993003.01215-2022

“This was a really well-designed study, and the authors should be congratulated on a trial which prioritised quality of life as the primary outcome measure, which is the purpose of MPE treatment. This study shows once again that IPCs (even when aggressively managed with daily drainage, intrapleural talc and all ultrasound directed) do not have the same pleurodesis success rate as inpatient pleurodesis – but both interventions improve symptoms and quality of life, without one clearly superior to the other. This is the third randomised trial comparing inpatient pleurodesis to IPC – and as TIME2 and AMPLE1 showed, demonstrated no superiority in any symptom outcome, but an increased rate of adverse events using IPCs compared with talc. As such patient choice and shared decision making remain paramount in the management of MPE”

Prof Najib M Rahman
Consultant Respiratory and Pleural Physician, Oxford Centre for Respiratory Medicine
Director, Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford
National Speciality Lead for Respiratory, NIHR Clinical Research Network

Prehabilitation

Pre-treatment optimisation of elderly lung cancer patients with frailty

With an aging and increasingly frail population and the advent of national lung cancer screening, we expect to see an increase in surgical resection rates in this higher risk group. Frailty is increasingly recognised as an independent risk factor for post-operative major morbidity and mortality, and this poses a significant challenge to lung cancer services. Prehabilitation has been successfully delivered as part of many surgical programmes, including NSCLC resection and has been shown to improve post-operative outcomes. In this study by Goldsmith et al the authors sought to study the impact of their prehabilitation program on frailty and other important outcomes.

The study included 314 patients of whom 137 had a Frailty Index (FI) >3. Patients received two weekly sessions of 70 minutes over a 2–4-week period, under the supervision of a cardiothoracic physiotherapist, alongside home exercises to be conducted three times daily.

Patients with a baseline FI>3 had a worse ECOG PS, lower 6-minute walk test (6MWT) and higher thoracoscores. 82.5% of patients with an FI >3 were considered unfit for surgery vs 33.3% with FI<3. Following prehabilitation, 6MWT improved from 218m to 306m (p = 0.04), PS 0-1 group classification improved from 20% to 41% (p <0.01) and the proportion considered unfit improved from 82.5% to 4.8% (p <0.01). There were some differences in surgical management, with 52.5% and 26.3% of FI>3 patients undergoing lobectomy and wedge resection, respectively compared to 69.5% and 17% in FI<3. Following surgery, there were no significant differences in major complication rates (8.8% in FI>3 vs 9.2% in FI<3), length of hospital stays (7 vs 8 days) or 30-day mortality (3.7% vs 0.7%). Similar findings were observed in further subgroup analysis of the >70 years old with FI>3 group, compared to <70, FI<3.

 

The authors conclude that Prehab can optimise high-risk frail and elderly patients allowing them to undergo lung cancer surgery safely.

 

DOI: 10.1186/s13019-023-02433-9

“It is encouraging to note that for patients with clinically significant frailty, there was a clinically and statistically significant improvement in fitness following prehab. This, alongside the feasibility of optimising elderly patients with frailty are important findings. The study findings align with anecdotal observations we have found in the Greater Manchester Prehab4Cancer and recovery programme (P4C), where we have also seen older participants demonstrate significant improvements in their Clinical Frailty Scale (CFS) scores and fitness scores (6MWT) following prehab (unpublished data).

Future studies would benefit from including prehab protocol adherence data, as this will enhance the analysis of study findings. Furthermore, qualitative data from older participants regarding their experience and acceptability of prehab would enrich this area of research. Finally, this study, alongside our learning from the P4C service implementation, further supports the need for wide education to clinicians who may refer to prehab services and/or have the opportunity to advocate prehab interventions to their patients. Some may not feel such a referral or advice is applicable for elderly patients, with significant frailty. The opposite is true and prehab could perhaps gain greater momentum across healthcare service delivery in the context of improving the outcomes of those experiencing frailty, even reversing the experience of frailty in some instances. Further reading for those interested can be found here

Zoe Merchant (Highly Specialist Occupational Therapist)
AHP Clinical Lead – GM Prehab4Cancer and Recovery programme
GM TLHC Programme Manager
National Prehab Guidance ‘Health Economics subgroup’ co-chair

Medical Oncology

Consolidation Therapy in Stage III EGFR Mutant NSCLC

In this international retrospective study, Nassar and Kim et al assessed the clinical efficacy of three approaches to consolidation among patients with EGFR mutant NSCLC following definitive chemoradiation. While the PACIFIC trial demonstrated that adjuvant durvalumab immunotherapy (IO) improved 5-year overall survival by 10% from 33% to 43%, subsequent subgroup analyses identified that patients with EGFR mutations did not benefit. This was also reflected in metastatic disease trials such as KEYNOTE-789 where the addition of IO to chemo did not improve outcomes in EGFR mutant NSCLC. Given the low numbers of cases and the post-hoc nature of the PACIFIC sub-analysis, national guidelines continue to support IO consolidation in patients with actionable mutations. Some physicians recommend the EGFR-targeted osimertinib tyrosine kinase inhibitor (TKI) therapy in this setting, despite the lack of direct evidence for this. Nassar and Kim et al sought to examine this gap in the literature by undertaking this large retrospective analysis of consolidation therapy.

Patients with stage III EGFR mutant NSCLC treated with definitive chemoradiation at 24 institutions between 2015 and 2022 were retrospectively enrolled. The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS) and toxicity data was also collected. Among the 136 recruited patients, there were no differences in baseline characteristics or radiotherapy, but the TKI group contained more advanced disease cases, and had a shorter duration of follow-up available. Common mutations (exon 19 deletion and L858R) comprised the majority of cases (96%).

Median PFS was best for TKI (not reached) followed by IO (13 months) and observation (10 months). The hazard ratio for PFS compared with observation for TKI was 0.14 and IO was 0.67. Comparing TKI against IO, the hazard ratio was 0.20 in favour of TKI. The incidence of brain metastases was lowest for TKI (7%) followed by observation (11%) and IO (17%). Interestingly, PFS was not associated with tumour PD-L1 expression. There was no significant difference in OS between the 3 groups, although the TKI median OS has not yet been reached. With respect to toxicity, the crude rates were similar for TKI and IO at 52% and 48% respectively, but the grade 3+ event rate was lower in TKI treatment (6% vs 18%) and was most commonly pneumonitis in both active treatments.

 

The authors conclude that consolidation durvalumab is not useful in EGFR mutant NSCLC as evidenced by the similarity in PFS, brain metastases and OS with observation. They suggest that consolidation TKI is a strong potential future standard of care given the superior disease control in this study, despite worse baseline disease and shorter follow-up. Furthermore, the toxicity profile of TKI was better than IO.

“PACIFIC was a huge leap forward for the management of unresectable stage 3 NSCLC.  However, the benefit of adjuvant Durvalumab in patients with driver mutations remained questionable.  Despite being a retrospective study with relatively small number this important paper addresses several key areas for patients harbouring EGFR mutations.  Regardless of PDL1 expression an immunotherapy approach for these patients is likely to confer no real benefit – and may actually cause harm at the point of recurrence when patients are exposed to an EGFR TKI.

The paper alludes to a significant PFS benefit for consolidative Osimertinib in this setting.  The press release from the LAURA clinical trial suggests this benefit is confirmed in the prospective Phase 3 randomised trial and we eagerly await publication of the trial results.  Hopefully this will open the door to precision oncology for our unresectable stage 3 patients.”

Dr Shobhit Baijal
Consultant Medical Oncologist
The University Hospitals Birmingham NHS Trust

Clinical oncology

Radiation-Induced Lymphopenia for Protons versus Photons

Image copyright Therapeutic Advances in Medical Oncology used under a CC BY-NC-ND 4.0 DEED license.
OARs of lymphopenia. (A) Red: GTV; blue: heart and blood vessel; yellow: lung; green: body. (B) Red: spinal cord; yellow: spleen. As the thymus gland gradually shrinks with age, it is not shown here. GTV, gross tumor volume; OARs, organs-at-risk.

In a multicentre retrospective study, Cortiula et al evaluated the rate of haematological toxicity following definitive concurrent chemoradiation for unresectable stage III NSCLC. Radiation-induced lymphopenia (RIL) is common in this cohort because lung tumours are frequently adjacent to lymphoid organs such as the bone marrow, lymph nodes and spleen meaning these organs receive incidental irradiation. Further, the large amount of vasculature in the thorax (e.g. heart, great vessels) leads to considerable exposure of the circulating lymphocytes to radiation over the course of the few minutes that it takes to deliver a daily fraction of treatment. As lymphocytes are highly radiosensitive, even low doses of incidental irradiation can lead to a depletion of their number, especially in the context of concurrent cytotoxic chemotherapy which characteristically suppresses the bone marrow.

RIL is associated with worse survival, including via mechanisms such as decreased tumour control and increased opportunistic infections. In the era of post-chemoradiation consolidation immunotherapy, RIL is also particularly relevant since the reduction of immune system tolerance of tumour cells underpinning immunotherapy, is largely mediated via lymphocytes. This has been demonstrated in preliminary data suggest that RIL can negate the effect of immunotherapy. In contrast with classic radiotherapy, which is based on X-ray photons, which generally pass directly through the body, proton radiotherapy leads to reduced ‘exit dose’ since the protons stop within the target. Theoretically proton therapy may therefore reduce the amount of chest irradiation, and there the risk of RIL, however proton therapy is highly restricted at present due to its limited clinical evidence and greater expense.

Patients with stage III NSCLC treated with curative-intent radiotherapy with intensity-modulated photon therapy (IMRT) or intensity-modulated proton therapy (IMPT) at 4 Dutch and Italian centres between 2016 and 2022 were retrospectively analysed. Prior to analysis, patients were propensity-score matched to minimise differences between the two groups, resulting in the removal of 14 patients. The primary endpoint was rate of grade ≥3 lymphopenia.

Comparisons were made between 200 patients receiving IMRT and 71 receiving IMPT. The incidence of G3+ lymphopenia was significantly higher for IMRT than IMPT (67% vs 47, p=0.03). IMRT was associated with higher rates of PS ≥2 at both 21 days (26% vs 13%, p=0.04) and 42 days post-radiotherapy. This was reflected in reduced access to consolidation immunotherapy (64% vs 52%, p=0.01).

 

The authors conclude that compared with classic radiotherapy, proton therapy was associated with less lymphopenia, less declines in fitness and a higher probability of receiving immunotherapy.

 

DOI: 10.1016/j.radonc.2023.110019

“This study with all the caveats of retrospective, non-randomised data opens up major areas of discussion for the optimal management of stage III unresectable NSCLC. Radiation induced haematological toxicities including lymphopenia in this setting is well recognised but is frequently overlooked in daily clinical practice. Managing radiation-induced lymphopenia (RIL) will become more important as we strive to improve outcomes for this group of patients.

Equally important is the issue of proton versus photon radiation therapy in this setting. The authors report several other beneficial endpoints using protons such as improved early post treatment performance status and increased likelihood of receiving adjuvant immunotherapy. Major endpoints of overall survival and late toxicity need to be investigated. However, they state that randomised clinical trials of protons versus photons will be challenging especially as there is limited access to proton radiotherapy, so they raise the possibility of using computational or in silico models to try to answer these questions.”

Dr David Gilligan
Consultant Clinical Oncologist
Cambridge University Hospitals

We have a BTOG trainee group-chat on Slack!

Jon us to continue your thoracic cancer conversations.

The dedicated networking and introduction session for trainees at the BTOG Annual Conference is on Wednesday 17 April between 10am and 11am in Meeting Room 1 on Level 3, we look forward to seeing you all there!

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