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The Potential Utility of Studying Metastatic Disease

The Potential Utility of Studying Metastatic Disease

In this issue of ONCOLOGY, Anacak et al present an interesting study examining the natural history of subclinical metachronous or synchronous metastases in patients with newly diagnosed cancer.[1] They divide patients into three basic categories—those who clinically have no overt or subclinical metastases (cM0pM0), those who have no overt metastases but later develop clinical metastases that they assume are from subclinical metastases at presentation (cM0pM1), and those with clinically evident metastases (cM1pM1).

The authors then set out three hypotheses to test in these patients. The first is that the ratio of synchronous to metachronous metastases should be similar for different tumors. The second is that improvements in diagnostic tools should have caused the ratio of synchronous to metachronous metastases to increase over time. The third is that the fraction of patients with either synchronous or metachronous lesions should have declined over time due to increased screening and earlier diagnosis. To test these hypotheses, the authors analyzed Surveillance, Epidemiology, and End Results (SEER) data from 1973 and 1998 for several different cancer types.

First Hypothesis

The bulk of the data in this report is represented in a single illustration (Figure 3), in which the rate of cM0pM1 is plotted vs the rate of cM1 for 19 different cancers from 1973 and 1998. This plot shows a modest correlation (r = ~0.5) between these two rates, which the authors believe is consistent with hypothesis number 1. However, it is not until the y axis is normalized to all patients (cM0pM1/cM0) that a strong correlation coefficient is seen (r = 0.86). The rationale for this normalization is stated, but not entirely clear.

Without this normalization, we feel that the data more likely demonstrate that the biology of these tumors is not the same—some tumors are easily identified and metastasize late (many melanomas), whereas others present with early metastases (pancreatic cancer). Therefore, there is no biologic reason to expect that the synchronous-to-metachronous rates should be the same across tumor types.

Second Hypothesis

In terms of the second hypothesis, we are not surprised that this was disproved by the data at hand. Imaging technology has dramatically improved over the past 25 years. This has led to our ability to radically improve diagnosis of both synchronous and metachronous lesions. Additionally, there have been wide-ranging improvements in the treatment of micrometastatic disease, and thus, the number of patients presenting with metachronous lesions is decreasing. This is illustrated by the SEER data in which 14 of 19 tumor types show a decrease in the rates of metachronous tumors between 1973 and 1998.

For example, there has been a steady rise in the incidence of colorectal cancer.[2] However, the incidence of synchronous and metachronous disease has decreased in this analysis of SEER data. Obviously, our ability to diagnose both of these has increased over time because of improvements in computed tomography and magnetic resonance imaging and the advent of positron-emission tomography (PET) imaging.[3] Additionally, with the advent of several new cytotoxic and biologic chemotherapeutics, the percentage of patients who develop metachronous disease has decreased substantially.[4]

One problem with SEER data in terms of identifying metachronous disease is that this characterization is represented as just as a yes/no data point in the SEER database. Presumably, finding metastatic disease is not affected by improvements in imaging, because the SEER data only show that metastases have occurred but do not address the timing of when they occurred. For tumors that spread early and for which we do not have good screening options (pancreatic and gastric cancers), we expect to see an increased incidence of synchronous disease being diagnosed. However, in tumors that spread late, improved imaging is less likely to have an impact on identifying synchronous disease.


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