Patients with cancer are usually staged based on the presence of detectable regional and/or distant disease. However, staging is inexact and cM0 patients may have microscopic metastases (cM0pM1) that later cause relapse and death. Since the clinical tools used to stage patients are fairly similar for different tumors, the ratio of the rates of metachronous to synchronous metastases should be similar for different tumors (hypothesis #1). Improvements in diagnostic tools should have caused the ratio of metachronous-to-synchronous metastases to have decreased over time (hypothesis #2). Finally, the fraction of patients with either metachronous or synchronous metastases should have declined over time due to increased screening and earlier diagnoses (hypothesis #3). To test these hypotheses, Surveillance, Epidemiology, and End Results (SEER) data from 1973-1998 were analyzed for 19 solid tumors. A linear relationship was seen between the rates of metachronous and synchronous metastases, with modestly strong correlation coefficients, consistent with hypothesis #1. Over time, changes in staging methods have not significantly altered the ratio of metachronous/synchronous metastases, contrary to hypothesis #2. Also over time, a decrease in the number of patients with metastases was found, consistent with hypothesis #3. Therefore, the rate of anticipated metachronous metastases can be estimated from the rate of clinically evident metastases at presentation. Changes in screening/staging of disease over time may have reduced the overall fraction of patients with metastases.
Cancer often spreads in a sequential fashion—from the primary (local) site, to regional sites (eg, lymph nodes), and then distantly. Patients with cancer are typically staged based on the presence or absence of radiographically/clinically detectable regional and/or distant disease. It is accepted that current staging evaluations, particularly imaging studies, are inexact. Many patients who are clinically without evidence of metastases (cM0) at the time of diagnosis actually harbor subclinical microscopic metastatic (pM1) disease that can later manifest as "recurrence" and lead to death. Therefore, clinicians must also rely on clinicopathologic features of primary cancers to help determine if systemic therapies are warranted (ie, if they are at sufficient risk for harboring micrometastases to potentially benefit from systemic therapies).
Three Staging Groups
Patients can be logically separated into three groups on a spectrum based on clinical stage as well as "real" or "pathologic" stage. For any given cancer site, patients can generally be sorted into one of three categories at diagnosis (Figure 1):
(1) Clinically without metastases and with no subclinical metastases (cM0pM0)—With effective local therapies, these patients can be cured of their disease. Adjuvant systemic therapies are unnecessary. With current staging methods, it is impossible to truly place a given patient in this group; however, by using clinicopathologic features at presentation (such as low disease burden and low histologic grade), clinicians often functionally place patients in this category and do not recommend adjuvant systemic therapy. An example of such a patient is a man with a T1c prostate cancer, Gleason score of 3+3, and prostate-specific antigen (PSA) level of 5.0 ng/mL. Since the risk of having (clinically relevant) metastatic disease is low in this patient, most clinicians would not recommend adjuvant hormone deprivation following primary local therapy with radical prostatectomy or radiotherapy.
(2) Clinically without metastases, but subclinical metastases are present (cM0pM1)—In this situation, no metastases are detected at initial imaging or staging, but patients later "develop" distant metastases. The metastases are initially subclinical; however, their size increases with time such that they are detected clinically through the course of the disease. Disease "recurrence" is diagnosed at that time. These metastases can be considered "metachronous." When clinicians are concerned by clinicopathologic features of a patient's disease (eg, T3b prostate cancer with Gleason score of 4+4, but with negative bone scan and negative computed tomography [CT] imaging), they may functionally place a patient in this group and recommend systemic therapies (eg, androgen deprivation in this example).
(3) Clinically evident metastases (cM1pM1)
In this situation metastases are clinically appreciated at the time of initial staging procedures. These metastases can be considered "synchronous." A small fraction of these patients may actually be without metastases (eg, false-positive scans for metastases—a state of being cM1pM0). As this fraction is typically small, it is excluded from the discussion.
A more detailed segregation of patients within these three groups is illustrated in Figure 2. Consider a hypothetical cohort of patients at the moment their primary tumors come into existence. At that time, 100% of patients are cM0pM0. Over an interval of time, a portion of these patients develop a small burden of metastatic disease. Over successive time intervals, the fraction of patients who are cM0pM0 declines as the fraction of patients with metastatic disease increases. Further, the burden of metastatic disease within this group of pM1 patients also increases over time. At late time intervals, the number of cM0 patients approaches zero. In Figure 2, 10% of patients are assumed to develop metastases during each of the successive time intervals, and the metastatic burden among the pM1 patients is assumed to increase by 1 log. This assumption is made for convenience, and the methods and results described in this analysis are not dependent on the hypothesized details of tumor growth kinetics.
Within the framework illustrated in Figure 2, patients can be segregated into cM0pM1 and cM1 based on the sensitivity of the clinical/radiologic tools available to detect metastatic disease. Larger metastatic burdens are generally more readily clinically detected (cM1) than are smaller burdens of metastatic disease that are often clinically undetectable (cM0pM1). For diseases where the transition from pM0 to pM1 appears to be rapid (eg, due to an aggressive biologic behavior), a larger fraction of patients will be either cM0pM1 or cM1 at presentation. Conversely, for diseases where metastases are less common, smaller fractions of patients will be either cM0pM1 or cM1 at presentation.
Thus, if one compares across different diseases, there should be a relationship between the rates of patients presenting as cM0pM1 and those presenting as cM1. Alternatively stated, for diseases where a relatively large fraction of patients present with metastatic disease, a relatively large fraction of cM0 patients probably harbor subclinical microscopic metastatic disease (cM0pM1).
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