PII: S0003-4975(99)01228-X

Abstract

There are a few papers every year that can potentially revolutionize the care of patients with lung cancer. This paper is one of them and should be listed as one of the classics from The Annals of Thoracic Surgery. Moreover, to have conceived the idea of bone marrow biopsy as a potential prognostic indicator in lung cancer in 1989 at a time when even “systemic mediastinal lymphadenectomy” was not even considered standard underscores the vision and genius of this thoracic group. The findings in this manuscript that two or more micrometastases found on numerous bone-marrow biopsies is an independent predictor of overall survival from completely resected patients with lung cancer is, in my opinion, going to change our whole approach to the determination of the M status in this patient population. The ramifications are profound and immediately force us to accelerate technology in diagnostic regards: (1) how can we develop better imaging techniques to see these cells without invasive biopsy; (2) is there a correlation between density of these cells and as yet undefined immunologic epitopes which may reflect their presence in the serum; (3) how does the presence of these cells correlate with tumor DNA detected in the serum, which is just now being investigated; and (4) if these peripheral markers hypothesized in (2) and (3) correlate with bone-marrow disease, do they have the same prognostic import as bone-marrow disease? Obviously, these stunning findings force us to reevaluate our treatment strategies for “early stage” lung cancer. Independent of the size of the tumor in node-negative patients, the presence of these cells had a negative prognostic determinant. Moreover, the presence of these cells does not correlate with lymph node status, alerting us that early pathways for tumor dissemination may be different with regard to their influence on survival. Careful analysis of the data reveals that the percentage of patients having bone-marrow disease was about equal stage for stage. If that is so, then the group at most risk, or perhaps of most benefit if therapeutic decisions are guided by bone marrow positivity must be in what we consider “early stage patients”. These findings scream out that a more aggressive treatment option other than local therapy alone must be employed, and induction initiatives like BLOT as well as those reported by DePierre (Proceedings of ASCO, 1999, abstract 1792) may be just what the doctor ordered. What we learn from the biologic implications of this study could potentially lead to novel translational therapies. The finding of these cells in the marrow is a characteristic of the primary tumor biology, not so much the stage. If their presence does not predict bony metastases, and if the cells are dormant in the marrow and have low proliferation index, yet patients end up with systemic metastases (perhaps from the same clone), then we must surmise that the presence of these cells in the marrow is a surrogate for systemic disease. Possibly of greater relevance is to find out what is in the marrow that keeps these cells in check or even makes them disappear but does not have a systemic purging effect. Obviously, these cells represent the more aggressive clones admixed in the primary tumor. If we can characterize these two or three cells (that represent many more which are silently growing in other sites of the host) by looking for differences from either normal cells or other tumor cells in the patient using subtraction hybridization, phage display, or array technologies, maybe we could develop more precise strategies based on differential characteristics of these cells. Some of the most profound advances in therapies develop when clinicians describe a novel finding. Why? Because the finding stimulates translationally oriented bench workers to collaborate in the scientific feeding frenzy. I would predict that this paper will turn on a lot of light bulbs and generate such collaborative goldmines.