GR01.03 Nodal Status of the Primary Disease?

Abstract

Oligometastases from non-small cell lung cancer (NSCLC) can be classified as synchronous, which are diagnosed at the same time as the locoregional disease, or metachronous, developing after (successful) treatment of the locoregional disease. The title of this presentation implies that the nodes are present at the time of treatment, so the focus will be restricted to the treatment of synchronous oligometastases. In the absence of a universally accepted definition of oligometastatic disease we will assume that the term can be used where there are up to five metastatic sites. Nodal involvement as a prognostic factor in patients with oligometastatic disease. The earliest reports of attempting to improve survival outcomes for patients with limited metastastic disease were in patients with brain metastases either by resection (1) or by resection or stereotactic radiosurgery (2). Five year survivors were observed, vindicating aggressive treatment in this subset of stage IV patients with NSCLC, but patients with regional node involvement appeared to have worse survival than patients with N0 disease. This was confirmed in a subsequent large multicentre individual patient data meta-analysis reported by Ashworth et al of 757 patients who were treated with ablative treatments to all sites of disease (3). Factors that were important for survival in the meta-analysis were metachronous versus synchronous and histology (favouring adenocarcinoma) as well as N stage. Using recursive partitioning analysis, Ashworth et al were able to group patients with synchronous metastases into an intermediate risk group with N0 disease and a 5 year survival of 36.2% versus a high risk group with N1 or N2 disease and a 5 year survival of 13.8%. Why should regional node status be a prognostic factor in patients who already have distant metastatic disease? Most likely it is because nodal involvement is a surrogate for the volume of metastatic disease that may have been underestimated in the pre-PET era. Is regional nodal involvement a contraindication to an aggressive approach? Although Hu et al (2) recommended against an aggressive approach to the locoregional disease in patients with stage II or III NSCLC, the fact that 3 year survivors were observed in their cohort and 5 year survivors in the meta-analysis suggests that it is an option that should be discussed considered. in a retrospective study by Flannery et al if the thoracic disease was not treated definitively, survival at 5 years was 0% compared with 34.6% for surgical resection or chemoradiation (P < 0.0001) (4). Patients with N0 or N1 disease (grouped together) had longer survival than patients with N2 or N3 disease, but this was not statistically significant. A prospective phase II trial treated patients with up to 5 oligometastatic sites with chemotherapy followed by chemoradiation to the primary and involved nodes plus SABR or high dose radiotherapy (60 Gy in 30 fractions) to the metastases was associated with a median survival of 28 months, but there was no difference in survival whether nodes were or were not involved (5). Does nodal status influence whether locoregional disease should be treated by surgery, SABR or (chemo)radiotherapy? This will depend on the patient’s fitness for surgery, and the anatomical extent and location of disease. We have no evidence to support any one strategy. We use the same principles to select treatment to the locoregional disease as if there were no oligometastatic disease present. In the Ashworth meta-analysis, surgical management of the primary was a favourable prognostic feature with a hazard ratio of 0.74 (95% CI: 0.55 – 1.00) on univariable analysis, but not on multivariable analysis (3). In the first randomized trial in patients with NSCLC oligometatases the use of ablative treatments did improve disease free survival in patients with NSCLC who had up to 3 metastases and no evidence of progression after systemic therapy. (6) In this small trial, nearly all patients had synchronous oligometastases. Treatments used for the primary disease after first-line systemic therapy included surgery, stereotactic ablative body radiotherapy (SABR) and chemoradiation. Any involved regional nodes were regarded collectively as one “oligometastatic site”. There was no significant difference in progression-free survival comparing patients with N0-1 disease versus N2-3. Conclusion Where a patient has synchronous oligometastatic disease that is amenable to ablative therapy, definitive treatment to the primary site and any involved regional nodes taking into account the patient’s general condition and disease stage is a reasonable option, regardless of nodal stage.