Abstract

Background

Oligometastatic disease (OD) is usually defined arbitrarily as a condition in which there are ≤ 5 metastases. Given limited disease, it is expected that patients with OD should have better prognosis compared to other metastatic patients and that they can potentially benefit from metastasis-directed therapy (MDT). In this study, we attempted to redefine OD based upon objective evidence that fulfill these assumptions.

Discussion

The concept of OD envisioned by Samuel Hellman in 1995 has attracted much attention in recent years [1,2,3,4,5, 8, 11, 12]. It hypothesizes an interim condition in which a tumor has spread to only a few sites and cure by MDT may be possible. Unfortunately, there is no reliable biomarker for OD and no universally accepted definition [10]. In most studies, OD was arbitrarily defined as a condition in which there are five metastases or less in imaging studies that are technically treatable with MDT [7]. In this study, we suggest adding metastases clonal origin to the definition of OD to identify those patients with greatest chance for cure by MDT.

Tracking a given metastasis’ clonal origin is not an easy task. It requires retrieval of tumorous tissue and complex genetic and epigenetic studies [13,14,15]. However, in a previous study it was showed that the relatively straightforward analysis of metastases number and diameter may provide readily available information regarding clonal origin by differentiating between linear and parallel patterns of appearance [9]. In brief, the linear model asserts that when a malignant clone gains the capabilities needed to become a metastasis (invasion, angiogenesis etc.); a cluster of metastases disperses from this clone. Since all these metastases have the same clonal origin and commission time, a similar growth rate is expected at any landing site. Thus, all metastases originating in that clone have a similar diameter in any specific organ at any time point. Additional clones may reach this maturity and spread as clusters of metastases but for each cluster, a distinct diameter of all its metastases is expected. By contrast, the parallel model suggests early spread of disseminated tumor cells (DTCs). These cells mature to metastases independently in the target organs and are therefore expected to be at varying diameters. LPR quantitatively displays how much of the tumorous spread was linear and how much parallel. LPR =  + 1 means unmixed linear spread and LPR = − 1 unmixed parallel.

Clearly, the ideal patient to be defined as possessing OD will have a pure a linear (LPR =  + 1), monoclonal, single cluster of metastases, preferably with only a few tumors technically permitting MDT. Patients with a linear multi-clonal or parallel metastatic spread have a more genetically diverse disease and are expected to respond less well to MDT. It is therefore anticipated that a patient with “true” OD will demonstrate a better prognosis compared to patients with non-OD.

In this study using chest CTs of patients with lung metastases originating in ten different malignancies, we showed that patients with a single metastasis or a single cluster of metastases demonstrating diameter variations of 1 mm or less can be classified together into a group possessing significantly better prognosis compared to other patients with metastatic disease (Table 1 and Figs. 1a and 2a). We also showed that if metastases diameter is ignored, the prognosis of patients with 2–5 metastases is similar to that of patients with 6–10 metastases; supporting the concept the five metastases upper limit requirement of OD is probably not biologically true. (Fig. 1b).

Not all tumor types showed the same prognostic dependence on the number of metastases and metastatic clusters. Metastases number had no significant prognostic impact in cancers of the breast, prostate, thyroid, pancreas, and stomach. This is probably due to the small number of patients with a single metastasis in these tumors (only 2, 1, 0, 7, and 3 patients with these tumor types respectively). Metastatic cluster number had no significant impact on the prognosis of patients with tumors of the bladder, breast, melanoma, prostate, and stomach. This could also stem from a small number of patients with a single metastases cluster (only 3, 6, 4, 10, and 8 patients with these tumor types respectively).

Variability of metastases number between clusters and LPR also showed a highly significant impact on OS (p < 0.0001). Both parameters are related to genetic diversity of the metastases. This observation is important scientifically and supports the previous conclusion. However, since these parameters are less intuitive and require computerized calculation, it is suggested not to include them in the definition of the OD. As stated earlier, a single cluster means LPR =  + 1. In search of confounders to this model, the features of patients with single and multiple clusters of metastases were compared (supplementary material S5). Tumor’s origin and patients’ age were similar but there were significantly more men than women in the single cluster group (66.4% Vs. 52.9%, p = 0.06). Gender itself had no significant effect on OS (supplementary material S6) so the significance of this finding is not clear and merits further studies.

The model presented here, with the suggestion of qualifying only patients with a single metastatic cluster (representing a single clone) in the definition of OD, is obviously oversimplified. Yet it could be useful for planning clinical research in OD and may potentially provide better results compared to the poor results obtained with the standard definition of five metastases or less [3,4,5, 8].

We acknowledge that this study has several notable limitations:

1. 1. Although patients with a single cluster of metastases showed significantly better prognosis, this may not automatically translate into better response to MDT.
2. 2. Metastases growth rate may be influenced by proximity to anatomical structures; thus, metastases originating in a single clone may grow at different rates and mimic several clones.
3. 3. Similarly, an earlier slow growing clone can reach the same diameter as a later but faster growing clone. In this way, several clones may mimic a single clone. Given the improved survival of patients with a single cluster noted according to the proposed model, this condition is unlikely.
4. 4. This study was performed on lung metastases only. Measurement of metastases diameter in other organs is less straightforward and may show different results. Thus, further assessment of these alternative tumor microenvironments will be necessary.
5. 5. Primary tumor control and metastases outside the lungs were not considered in the analysis. As shown by Niibe et al. patients with 1–5 metastases after control of the primary tumor (oligo-recurrent disease) have good prognosis with three-year OS of 64% after SABR [12].
6. 6. Only metastases largest diameter was considered here, due to the simplicity of its measurement. Future studies assessing the potential role of lesion volume and perhaps using deep learning techniques are encouraged.

In summary, this study addresses OD from a biologic/pathophysiologic rather than surgical/anatomic point of view. We demonstrate that patients with a single cluster of metastases, potentially originating from a single clone, even with more than five lesions, have significantly better prognosis compared to patients with polyclonal disease. Accordingly, we propose including monoclonality in the definition of OD. The upper limit of metastases number should not be set arbitrarily and should be determined by the technical capabilities of the MDT. These criteria can potentially improve patient selection for MDT and provide a higher percentage of curative procedures for patients with metastatic disease.

Representative scans of patients diagnosed with a few metastases with similar diameters representing a single (presumably monoclonal spread) cluster. a-liposarcoma, b-pancreas, c-stomach. These patients are suitable for inclusion in an oligometastasis trial. Patients were diagnosed with few metastases but with different diameters (presumably representing multiclonal spread) d-colorectum, e-melanoma, f-osteosarcoma. Despite having only a few metastases, these patients may not be suitable for inclusion in an oligometastasis trial,

Source: springer.com