Speaking at Hospital Healthcare Europe’s recent Clinical Excellence in Respiratory Care event, Dr Zaheer Mangera shared insights into the evolution of the neoadjuvant lung cancer pathway, its benefits and challenges, and notable changes to the TNM standards used to classify malignant tumours.
Click here to read part one of Dr Mangera’s overview of lung cancer management and diagnosis, including insights into the latest guidance, diagnostic and treatment targets and a deep dive into lung cancer screening and incidental findings.
How has the management of patients on the lung cancer pathway changed with neoadjuvant therapy?
The neoadjuvant lung cancer pathway has triggered a paradigm shift in how we’re treating our patients. About 20-25% of patients with non-small cell lung cancer have resectable disease at the time of presentation, yet 30-55% of patients undergoing curative surgery have recurrence.
What can we do to try to improve the cure rates in these groups? Historically, there’s always been some modest success with both adjuvant and neoadjuvant approaches.
A big study, CheckMate 816, looked at patients with Stage 1B lung cancer, with a tumour size of over four centimetres without any nodal metastases, to anything up to Stage 3A.
The researchers looked at patients deemed to have resectable disease at the time of multidisciplinary team (MDT) input, with a very good performance status of zero or one. This would be the first instance of having cancer treated, and they shouldn’t have an anaplastic lymphoma kinase/epidermal growth factor receptor (EGFR) mutation.
They were offered nivolumab immunotherapy, regardless of their programmed death-ligand 1. Alongside, they had a platinum-based chemotherapy versus just chemotherapy alone. They then restaged patients then proceeded to surgery.
The primary endpoint was looking at event-free survival and pathological response to treatment. It found clear difference in the event-free survival curve between those who had nivolumab with chemotherapy versus those who had chemotherapy alone. A statistically meaningful difference was sustained well beyond the three-to-four-year period.
It’s now part of NICE guidance, albeit not part of the lung cancer guidance specifically, as it’s a separate NICE technological appraisal (TA876). It’s really made us think about how we can get these patients through a pathway and the challenges involved.
The first patient on this pathway at my hospital had excellent response to the neoadjuvant treatment, then went on to have an uncomplicated surgery and now is just on standard follow-up.
What are the challenges with the neoadjuvant pathway?
Trying to give chemotherapy before surgery makes an already complex pathway even more complex. It lengthens the pathway considerably, because those three cycles can take over two months to get through, plus the required follow-up scans.
So, although the first treatment would have been given, the time it takes for you to then close the loop at your MDT and say the whole treatment has been finished is definitely elongated.
For most patients, if you offer them surgery, they want a tumour out. Of course, there are lots of other tumour groups where you give neoadjuvant treatment and so having discussions about the process is not new to the oncologist, but it’s new to our surgeons.
There are risks of toxicities, although the trial data reports that the risk is not excessive, and patient tolerance is usually very high. It does mean we need to get an EGFR status as rapidly as possible. If you’re waiting a full four weeks for the EGFR status, before you can start treatment, it can mean considerable wait time to treatment in patients who have high-risk disease – those who are on the cusp of cure and not being cured.
We’re developing rapid EGFR pathways through our pathology labs where you can get the EGFR done more rapidly or even sometimes using the CtDNA blood tests.
And how do you standardise all these care plans and pathways across all cancer alliances and Trusts to ensure everyone is on board, everyone eligible for this treatment is getting it and to ensure we really accurately record it? It’s a real cornerstone of the National Lung Cancer Audit in how we collect our data now.
What else should we know about mediastinal signs and staging?
NICE guidance tells us that anyone with a PET-added lymph node, or a lymph node greater than 10 millimetres, should have an endobronchial ultrasound (EBUS). This sounds reasonable, but we know from different trials that there can be a discrepancy between PET and actual lymph node sampling itself, with false negatives and false positives.
This isn’t ideal if somebody is on the cusp between having radical surgery or needing combination therapy, for example, with neoadjuvant treatment. We know that even with PET/CT and EBUS, you can still miss some patients with nodal disease, and it only becomes evident at time of surgery when you’re removing the entire node.
Accurate staging is important. There are different ways of deciding which lymph nodes are higher risk. Sometimes it’s at ultrasonography when you recognise the risk. At the time of EBUS, you can accurately measure the size, which can be more accurate than CT, PET and PET/CT. And you may well see that the nodes are actually a conglomerate of nodes, for example.
The shape can be helpful: is it oval versus round? Are the margins clear? This is a really good one because very often when you can’t find the lymph node or you can’t really see the margins, it can sometimes be reassuring compared to where you see distinct margins.
Is it homogenous, does it echo-signal consistently throughout or have subtle changes between one area and the next? Is the central hilum structure present or is it absent? Is there any evidence of necrosis?
In future, we’re largely trying to transition to any lymph node over 10 millimetres on CT being biopsied, as well as any lymph node with fluorodeoxyglucose avidity and any lymph node with high-risk features. The only way you can do that is by doing an EBUS.
How is the next edition of the TNM Classification of Malignant Tumours changing?
The TNM 8th edition is what we’re using at the moment and the TNM 9th edition, which is due to go live imminently. The changes are reasonably subtle and there’s no significant ground shift in how we stage lung cancers.
First of all, N2 lymph nodes are going to be split into N2a and N2b. Currently it’s just N1, N2, N3 and we’re now going to have a sub-category for lymph node station N2, with N2a being single station involvement and N2b being multiple station involvement.
It doesn’t really comment too much on size here, so it still does need a little bit of working out in MDT with what you’re going to do with different lymph node groups and how it may or may not change your management and approach to the patient.
Then you’ve got your M stages. M1a and M1b are largely unchanged but M1c is split into M1c1 and M1c2.
M1c1 is multiple extrathoracic metastases in a single organ system, so multiple liver or brain metastases, rather than single metastases, and M1c2 is extrathoracic metastases in multiple organ systems.
This will subtly change the staging and may make a difference to what your approach might be. Having metastases doesn’t mean you don’t have radically treatable disease, and our oncology teams have specific MDTs for patients with metastatic disease and stereotactic ablative radiotherapy MDTs.
More and more of these metastatic diseases can be treated and that’s why it’s important to differentiate between M1b, M1c1 and M1c2 because some of these patients, particularly with M1b may well still have radically treatable disease if it’s just a single metastasis in a single organ.
Dr Zaheer Mangera is a respiratory consultant and the lung cancer lead at North Middlesex University Hospital, now part of the Royal Free London NHS Foundation Trust in London, UK.
This article is part of our Clinical Excellence series, which offers valuable first-hand insights into how experts from renowned Centres of Excellence are pursuing innovative approaches to optimise patient care across the UK and Europe.
