Lung cancer classification should go further and distinguish between multiple extrathoracic metastases at a single organ system and those involving multiple organ systems, an Australian-led international expert group has recommended.

It follows an analysis conducted by the team, led by Professor Kwun Fong from the Prince Charles Hospital and the University of Queensland Thoracic Research Centre, Brisbane, on all metastatic categories ahead of the forthcoming ninth edition of the tumour, node, and metastasis (TNM) Classification of Lung Cancer.

The current descriptors developed by the International Association for the Study of Lung Cancer (IASLC) include M1a, M1b (single metastatic lesion), and M1c (multiple extrathoracic metastases in either a single organ or multiple organ systems).

However, writing in the Journal of Thoracic Oncology [link here], the researchers said further refinements were needed to improve capacity to indicate prognosis, considering the emergence of metastasis-directed therapies and immunotherapy.

These included two new definitions that divided M1c into:

• M1c1 (multiple extrathoracic metastases in a single organ system)
• M1c2 (multiple extrathoracic metastasis in several organ systems)

They drew from a database of 124,581 patients diagnosed between 2011 and 2019 with follow-up data until December 2021, of which 14,937 cases with NSCLC in stage IVA-IVB were available for analysis. This was a much larger dataset than the 8th edition’s, particularly with respect to the M category, the authors noted.

Multiple assessments demonstrated that patients with M1c who had metastases to a single extrathoracic organ system were prognostically distinct from M1c patients who had involvement of multiple extrathoracic organ systems.

The distinction was maintained after adjustment for potential confounders.

“Analysis of the much larger 9th edition database was able to demonstrate that the 8th edition M1c category consists of two prognostically distinct groups. Patients with tumours involving multiple metastatic lesions at one extrathoracic organ system (M1c1) have significantly better OS than patients with tumours involving metastatic lesions at multiple extrathoracic organ systems (M1c2),” they wrote.

“This was consistent in several statistical approaches and in multiple subset analyses. This is also consistent with external literature, albeit in a smaller retrospective cohort.”

“There is an argument for biological plausibility to support separating the M1c category into metastases at a single organ system vs multiple metastatic organ systems – the former could be expected to have a lower metastatic tumour burden and a better prognosis as suggested by clinical studies . Unfortunately, the current dataset did not allow us to adequately quantify metastatic tumor burden.”

They added: “We strongly recommend collecting granular lesion size and count data to inform analyses for the next revision of the TNM classification, specifically to enable an adequately powered analysis of the prognostic interaction of combined number of extrathoracic metastatic organ systems and number of metastases.

“This analysis will be important for validating empiric definitions of oligometastatic disease such as the popular definition of five or fewer metastatic lesions in three or fewer extrathoracic organ systems.”

The authors said their M1c1 definition recognised paired organs such as kidneys or adrenals as one organ system, as well as diffuse organs such as the skeleton.

They also said there were not enough data to make a call on whether there should be a limit to the number of metastatic lesions in a single organ system.

“Furthermore, this is likely a clinical issue that plays into judgment about the optimal treatment strategy for a patient, and not an issue amenable to dichotomisation according to a biologically inherent threshold,” they said.

The authors stressed that the introduction of the new M categories should not impact contemporary best practice, as stage classification could not address all nuances nor define the optimal treatment strategy for each individual patient.

The expert team proposed no changes to the current M1a or M1b categories.

They also recommended against including the size of largest metastatic lesion or the number of metastatic lesions as descriptors.

The research was supported by a grant from AstraZeneca, while some of the authors also declared having received funding from pharmaceutical companies.