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The definition of oligometastatic non–small-cell lung cancer (NSCLC) has historically been based on the number of disease sites. However, this number has varied substantially in the literature, ranging from a solitary metastasis to up to five lesions. In fact, these relatively crude definitions belie a broader biologic state that extends from locally advanced disease to uncontrollable systemic disease burden. The unique state of metastases was proposed by Ralph Weichselbaum and Samuel Hellman in their landmark 1995 review,1 which has since been updated to incorporate more recent supporting data.2 The authors apply the “seed and soil” hypothesis to propose that during the multiple stages of systemic spread, including altered cell adhesion, survival in the circulation, and seeding/propagation in a distant site, any disruption in this process could lead to a more limited metastatic state.

Another way of describing this process is in a framework similar to Darwinian evolution. That is, several factors influence the survival of a tumor cell, including local regulators (hypoxemia, metabolism), systemic features (growth factors, immune response), and external exposures/lifestyle and inherent genetics (Fig. 81-1A).3 The balance of positive and negative factors determines whether clinically significant metastases will occur in a specific organ. In some patients, these features are favorable in multiple organ sites and manifest in polymetastatic disease. In others, tumor propagation may occur in one organ, or in only one lesion, while the remainder of the cells remain confined to the primary site, unable to exit the circulation, or remain dormant in a distant site as the tumor is unable to proliferate and form detectable foci of disease. It is in these scenarios that oligometastases occur (Fig. 81-1B).

Figure 81-1

Clonal evolution in cancer progression. Multiple internal and external factors affect cell survival and systemic spread. A. Schematic of the multiple influences of tumor cell survival. B. Clonal evolution as a driver for cell selection and metastatic spread. The parallels to a Darwinian evolutionary theory are depicted in the bottom right panel, taken from Charles Darwin’s notes. (Reproduced with permission from Greaves M, Maley CC. Clonal evolution in cancer. Nature. 2012;481(7381):306–313.)

Indeed, Weichselbaum and Hellman cite several preclinical and clinical analyses that support the paradigms of dormancy and temporal evolution. The latter concept describes a systematic order of progression in which systemic spread occurs in a hierarchical fashion. In one study, seven patients with pancreatic cancer underwent sequencing of multiple metastatic sites, including the liver, lung, and peritoneum. The investigators ultimately mapped the accumulation of mutations from the primary tumor to the metastatic site. In doing so, they proposed a clonal evolutionary process, which began at the primary site and progressed to subclones, first to the peritoneum, then the liver, and finally the lung.4 The implications of this finding are that ...

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